In fact, I would not test this patient at this time, and I would check if the transaminase level has normalized at a later time, since the most frequent cause, at least in children, is a transient elevation in the context of viral diseases (most frequently cytomegalovirus and Epstein-Barr virus). The minimal elevation of liver enzymes and the fact that it has a normal protein profile goes against chronicity... If I had to choose I would choose answer 5, which seems to me the least aggressive, and if I had to do analytical tests I would add the determination of alpha-1-antitrypsin (without CT) and markers of celiac disease, because celiac disease can also be associated with some hypertransaminemia.

In fact, I would not test this patient at this time, and I would check if the transaminase level has normalized at a later time, since the most frequent cause, at least in children, is a transient elevation in the context of viral diseases (most frequently cytomegalovirus and Epstein-Barr virus). The minimal elevation of liver enzymes and the fact that it has a normal protein profile goes against chronicity... If I had to choose I would [HIDDEN], which seems to me the least aggressive, and if I had to do analytical tests I would add the determination of alpha-1-antitrypsin (without CT) and markers of celiac disease, because celiac disease can also be associated with some hypertransaminemia.

12-year-old girl, only child of healthy, non-consanguineous parents. There is no personal or family history of interest. In the clinical examination to start a sports activity, you find a discrete hepatomegaly of normal consistency, so you request a blood test, which highlights an ASAT of 80U / l, ALAT 105 U / l, electrophoretic proteinogram with all protein fractions in normal range and negativity of serology for hepatotropic viruses. What should you rule out and what test would you indicate for it?

Deficiency of alpha 1 antitrypsin. Thoracic TAC to confirm emphysema.

Mucoviscidosis. Determination of chlorine in sweat.

Glycogenosis type VI (phosphorylase deficiency). Muscle biopsy.

Wilson's disease. Determine ceruloplasmin and copper in blood and urine.

Wilson's disease

There is no totally reliable test for Wilson's disease, but levels of ceruloplasmin and copper in the blood, as well of the amount of copper excreted in urine during a 24-hour period, are together used to form an impression of the amount of copper in the body. The gold standard—or most ideal test—is a liver biopsy. Ceruloplasmin Levels of ceruloplasmin are abnormally low (<0.2 g/L) in 80–95% of cases. It can, however, be present at normal levels in people with ongoing inflammation as it is an acute phase protein. Low ceruloplasmin is also found in Menkes disease and aceruloplasminemia, which are related to, but much rarer than Wilson's disease. The combination of neurological symptoms, Kayser–Fleischer rings and a low ceruloplasmin level is considered sufficient for the diagnosis of Wilson's disease. In many cases, however, further tests are needed.

You Only Find What You Are Looking for: Concurrent Alcoholic Liver Cirrhosis and Undiagnosed Wilson's Disease.

Wilson's disease (WD), a rare genetic disorder characterized by copper accumulation, leads to a spectrum of hepatic dysfunction including liver cirrhosis, fulminant liver failure, and chronic hepatitis. Its manifestations could involve musculoskeletal, hematologic, neuropsychiatric, or renal systems. We present the case of a 27-year-old female with a past medical history of alcohol use disorder who presented with acute confusion, worsening abdominal distension, bilateral lower limb edema, and jaundice.The initial presentation was concerning for acute alcoholic hepatitis and decompensated alcoholic cirrhosis attributed to ongoing heavy alcohol consumption. However, due to the patient's young age, the severity of presentation, and the pattern of liver enzyme elevation, further workup was conducted to rule out concurrent pathologies. Viral, autoimmune, and metabolic workups were unrevealing. Subsequently, low ceruloplasmin levels and elevated urinary copper levels led to a diagnosis of WD with concomitant alcoholic liver disease. The coexistence of WD and alcohol-associated liver disease (ALD) has not been well described in the literature. Laboratory testing including alkaline phosphatase (ALP), bilirubin, and serum aminotransferases provides the most rapid and accurate method for diagnosing ALD due to WD, given that the conventional screening tests such as ceruloplasmin are less sensitive and specific in identifying patients with acute liver disease secondary to WD.

Wilson Disease -- Evaluation

There is no completely reliable test for Wilson disease, but levels of ceruloplasmin and copper in the blood, as well as copper excreted in urine during a 24-hour period, are used to form an impression of the amount of copper in the body. The gold standard is a liver biopsy. First and second-degree relatives need to be screened for Wilson disease.

Acute liver failure

Initial laboratory analysis Prothrombin time/INR Complete blood count Chemistries Liver function test: AST, ALT, alkaline phosphatase, GGT, total bilirubin, albumin Creatinine, urea/blood urea nitrogen, sodium, potassium, chloride, bicarbonate, calcium, magnesium, phosphate Glucose Amylase and lipase Arterial blood gas, lactate Blood type and screen Paracetamol (acetaminophen) level, toxicology screen Viral hepatitis serologies: anti-HAV IgM, HBSAg, anti-HBc IgM, anti-HCV Autoimmune markers: ANA, ASMA, LKMA, immunoglobulin levels Ceruloplasmin level (when Wilson's disease suspected) Pregnancy test (females) Ammonia (arterial if possible) HIV status (has implication for transplantation) History taking should include a careful review of possible exposures to viral infection and drugs or other toxins. From history and clinical examination, the possibility of underlying chronic disease should be ruled out as it may require different management.

Spasmodic muscle cramps and weakness as presenting symptoms in Wilson disease.

Wilson disease (WD) is an autosomal-recessive disorder of hepatic copper metabolism that has tremendous variability in its presentation. Phenotypic diversity of the disease can lead to delayed diagnosis. We describe a case of WD in a 10-year-old boy presenting with 3 months of increasingly intense, spasmodic lower extremity muscle cramps. Physical examination revealed tenderness on calf palpation and dark flat lesions over his ankles, knees, and elbows. Initial testing revealed creatine kinase of 302 IU/L (normal 24-248 IU/L), hemoglobin of 8.9 g/dL (11.5-15.5 g/dL), aspartate aminotransferase of 114 IU/L (16-52 IU/L), alanine aminotransferase of 54 IU/L (2-30 IU/L), and myoglobinuria. Extensive evaluation of his myopathy, including MRI and muscle biopsy, was negative. Additional laboratory tests revealed a prothrombin time of 21.3 seconds (11.8-15.5 seconds), total bilirubin of 1.4 mg/dL (<1 mg/dL), direct bilirubin of 0.5 mg/dL (<0.3 mg/dL), albumin of 2.1 g/dL (3.1-4.6 g/dL), a reticulocyte percentage of 4.5% (0.5%-2.5%), a negative Coombs direct antibody test, ceruloplasmin of 3 mg/dL (21-51 mg/dL), and 24-h urine copper of 393 μg/24 h (15-60 μg/24 h). Liver biopsy showed patchy advanced fibrosis, mild inflammation, positive staining for copper, and a tissue copper concentration of 768 µg/g (10-35 μg/g). Brain MRI revealed symmetric intrinsic T1 shortening within bilateral basal ganglia. Trientene therapy was initiated for WD. Symptoms and laboratory abnormalities resolved and remain normal at 21 months' follow-up. Musculoskeletal involvement in WD is uncommon and typically defined as bone demineralization, arthropathy, or hypokalemic muscle weakness. In patients with unexplained musculoskeletal symptoms and hepatic abnormalities, a diagnosis of WD should be considered and appropriate evaluation initiated.

Gilbert Syndrome -- Evaluation

The provider should have a low threshold to consider other liver diseases that may cause hyperbilirubinemia before diagnosing Gilbert syndrome, as outlined above. If viral hepatitis is suspected, serologic tests for hepatitis A, B, and C should be considered. [44] [36] [45] If autoimmune hepatitis is a possibility, appropriate serology, quantitative immunoglobulins, and liver biopsy may be in order. [39] Laboratory evaluation, including serology with or without liver biopsy, is suggested for patients with suspected primary biliary cholangitis. [39] Testing for ceruloplasmin, serum, urine copper studies, liver biopsy, and slit-lamp examination for Kayser-Fleisher rings should be considered for suspected Wilson disease. [46] Finally, alpha-1-antitrypsin level and genotype would be appropriate if alpha-1-antitrypsin deficiency is a consideration. [47]

Liver Function Tests -- Results, Reporting, and Critical Findings

The results of liver function tests should correlate with the initial findings in a complete patient history and physical examination. A thorough review should include important questions regarding the patient's age, past medical history (diabetes, obesity, hyperlipidemia, inflammatory bowel disease, celiac sprue, thyroid disorders, autoimmune hepatitis, acquired muscle disorders, alcohol use disorder, medication use, toxin exposure, and family history of genetic liver conditions (Wilson disease, alpha-1-antitrypsin deficiency, hereditary hemochromatosis). [30]

Causes and evaluation of mildly elevated liver transaminase levels.

Mild elevations in levels of the liver enzymes alanine transaminase and aspartate transaminase are commonly discovered in asymptomatic patients in primary care. Evidence to guide the diagnostic workup is limited. If the history and physical examination do not suggest a cause, a stepwise evaluation should be initiated based on the prevalence of diseases that cause mild elevations in transaminase levels. The most common cause is nonalcoholic fatty liver disease, which can affect up to 30 percent of the population. Other common causes include alcoholic liver disease, medication-associated liver injury, viral hepatitis (hepatitis B and C), and hemochromatosis. Less common causes include α(1)-antitrypsin deficiency, autoimmune hepatitis, and Wilson disease. Extrahepatic conditions (e.g., thyroid disorders, celiac disease, hemolysis, muscle disorders) can also cause elevated liver transaminase levels. Initial testing should include a fasting lipid profile; measurement of glucose, serum iron, and ferritin; total iron-binding capacity; and hepatitis B surface antigen and hepatitis C virus antibody testing. If test results are normal, a trial of lifestyle modification with observation or further testing for less common causes is appropriate. Additional testing may include ultrasonography; measurement of α(1)-antitrypsin and ceruloplasmin; serum protein electrophoresis; and antinuclear antibody, smooth muscle antibody, and liver/kidney microsomal antibody type 1 testing. Referral for further evaluation and possible liver biopsy is recommended if transaminase levels remain elevated for six months or more.

Cirrhosis

Hereditary hemochromatosis usually presents with a family history of cirrhosis, skin hyperpigmentation, diabetes mellitus, pseudogout, or cardiomyopathy, all due to signs of iron overload. Wilson's disease is an autosomal recessive disorder characterized by low serum ceruloplasmin and increased hepatic copper content on liver biopsy, and elevated 24-hour urine copper. Patients may also have Kayser-Fleischer rings in the cornea and altered mental status. Indian childhood cirrhosis is a form of neonatal cholestasis characterized by deposition of copper in the liver. Alpha 1-antitrypsin deficiency is an autosomal recessive disorder of decreased levels of the enzyme alpha 1—antitrypsin. Cardiac cirrhosis is due to chronic right-sided heart failure, which leads to liver congestion. Galactosemia Glycogen storage disease type IV Cystic fibrosis Hepatotoxic drugs or toxins, such as acetaminophen, methotrexate, or amiodarone

Is 'routine' laboratory testing a thing of the past? Current recommendations regarding screening.

A 55-year-old man comes to you for a routine physical examination. He is a nonsmoker who takes no medications and has no signs of acute or chronic disease, and he has not seen a doctor in years. What blood work should you order for this patient? The authors of this article help you answer this question in light of recent advances in technology, restrictions in healthcare reimbursement, and increased sophistication in cost-benefit analysis for laboratory testing.

[Not Available].

Elevated transaminases in asymptomatic patients can be detected in more than 5 % of the investigations. If there are no obvious reasons, the finding should be confirmed within the next 3 months. Frequent causes are non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol, hepatitis B or C, hemochromatosis and drugs or toxins. Rarer causes are autoimmune hepatitis, M. Wilson and α1-antitrypsine deficiency. There are also non-hepatic causes such as celiac disease or hemolysis and myopathies in the case of an exclusive increase of ASAT. I recommend a two-step investigational procedure; the more frequent causes are examined first before the rare causes are studied. The value of the proposed investigations is discussed.

Alpha-1 antitrypsin deficiency

Diagnosis The gold standard of diagnosis for A1AD consists of blood tests to determine the phenotype of the AAT protein or genotype analysis of DNA. Liver biopsy is the gold standard for determining the extent of hepatic fibrosis and assessing for the presence of cirrhosis.

InternalMed_Harrison

implications when multiple tests are ordered. If N independent tests are performed on a specimen, then the probability that at least one result will be outside the reference range is (1–0.95N). The greater the number of tests ordered (even for a healthy individual), the greater is the likelihood of an abnormal result (Fig. 480e-1). If 20 independent tests are performed on a healthy subject, the probability of at least one abnormal result is almost two-thirds.

Hepatitis

Many people with autoimmune hepatitis have other autoimmune diseases. Autoimmune hepatitis is distinct from the other autoimmune diseases of the liver: primary biliary cirrhosis and primary sclerosing cholangitis. However, all of these diseases can lead to scarring, fibrosis, and cirrhosis of the liver. Genetic Genetic causes of hepatitis include alpha-1-antitrypsin deficiency, hemochromatosis, and Wilson's disease. In alpha-1-antitrypsin deficiency, a co-dominant mutation in the gene for alpha-1-antitrypsin results in the abnormal accumulation of the mutant AAT protein within liver cells, leading to liver disease. Hemochromatosis and Wilson's disease are both autosomal recessive diseases involving abnormal storage of minerals. In hemochromatosis, excess amounts of iron accumulate in multiple body sites, including the liver, which can lead to cirrhosis. In Wilson's disease, excess amounts of copper accumulate in the liver and brain, causing cirrhosis and dementia.

[Efficient diagnostics for elevated transaminases].

The diagnosis of the cause of elevated transaminases is carried out stepwise. First, a medical history is taken and a physical examination and sonography of the abdomen are performed. The second step includes laboratory tests for chronic hepatitis B and C, hereditary haemochromatosis, Wilson's disease, autoimmune hepatitis and alpha-1-antitrypsin deficiency. The third step comprises the identification of possible extrahepatic causes. Serological tests to exclude celiac disease should be first carried out when TSH and CK values do not yield an indicative finding.

Mild Hypertransaminasemia in Primary Care.

The liver enzymes, alanine transaminase (ALT) or aspartate transaminase (AST), are commonly used in clinical practice as screening as well as diagnostic tests for liver diseases. ALT is more specific for liver injury than AST and has been shown to be a good predictor of liver related and all-cause mortality. Asymptomatic mild hypertransaminasemia (i.e., less than five times normal) is a common finding in primary care and this could be attributed to serious underlying condition or has transient and benign cause. Unfortunately, there are no good literatures available on the cost-effectiveness of evaluating patients with asymptomatic mild hypertransaminasemia. However, if the history and physical examination do not suggest a clear cause, a stepwise approach should be initiated based on pretest probability of the underlying liver disease. Nonalcoholic fatty liver disease is becoming the most common cause of mild hypertransaminasemia worldwide. Other causes include alcohol abuse, medications, and hepatitis B and C. Less common causes include hemochromatosis, α1-antitrypsin deficiency, autoimmune hepatitis, and Wilson's disease. Nonhepatic causes such as celiac disease, thyroid, and muscle disorders should be considered in the differential diagnosis. Referral to a specialist and a possible liver biopsy should be considered if persistent hypertransaminasemia for six months or more of unclear etiology.

Cirrhosis

FibroTest is a biomarker for fibrosis that may be used instead of a biopsy. Other laboratory studies performed in newly diagnosed cirrhosis may include: Serology for hepatitis viruses, autoantibodies (ANA, antismooth muscle, antimitochondria, anti-LKM) Ferritin and transferrin saturation: markers of iron overload as in hemochromatosis, copper and ceruloplasmin: markers of copper overload as in Wilson's disease Immunoglobulin levels (IgG, IgM, IgA) – these immunoglobins are nonspecific, but may help in distinguishing various causes. Cholesterol and glucose Alpha 1-antitrypsin Markers of inflammation and immune cell activation are typically elevated in cirrhotic patients, especially in the decompensated disease stage: C-reactive protein (CRP) Procalcitonin (PCT) Presepsin soluble CD14 soluble CD163 soluble CD206 (mannose receptor) soluble TREM-1 Imaging

Subcutaneous panniculitis-like T-cell lymphoma with hemophagocytic syndrome successfully treated with cyclosporin A.

A 17-year-old girl previously in good health presented with a 2-month history of recurrent, high-grade fever; general fatigue; anorexia; a 10-kg weight loss; and multiple, painful, reddish skin lesions on the lower abdomen. Some lesions were ulcerated, with an oily yellowish brown discharge. A systemic review was unremarkable other than bleeding from the nose. Her medical and family histories were unremarkable. On examination, the patient was pale, jaundiced, and febrile (temperature of 39 degrees C). She had enlarged lymph nodes in the axillary and inguinal areas. There was moderate hepatosplenomegaly. Local skin examination revealed multiple erythematous, tender, and firm subcutaneous nodules of variable size (1-2 cm) on the lower abdomen. Some nodules were ulcerated, with oily yellowish brown discharge and overlying ecchymosis (Figures 1 and 2). Mucous membranes were free of lesions. Laboratory investigations showed pancytopenia, an elevated erythrocyte sedimentation rate (>80 mm/h), normal renal function tests, abnormal hepatic function tests (alanine aminotransferase 172 U/L, aspartate aminotransferase 229 U/L, alkaline phosphatase 725 U/L, and total bilirubin 100 mmol/L [normal range 0-18 mmol/L]), conjugated bilirubin 45 mmol/L (normal range 0-5 mmol/L), and high triglycerides 855 mg/dL (normal range 20-200 mg/dL). Prolonged prothrombin time, 26 seconds (normal range 13-16 seconds); prolonged activated partial thromboplastin time, 61 seconds (normal range 26-38 seconds); positive disseminated intravascular coagulation studies evidenced by low fibrinogen, 74 mg/dL (normal range 160-350 mg/dL); and positive fibrinogen degradation products were also noted. Throat, midstream urine, and blood culture results were negative. Serologic tests for syphilis, HIV, and hepatitis B and C viruses were negative. Epstein-Barr virus and cytomegalovirus serologic values revealed evidence of past infection. Tuberculin and Coombs tests were negative. The alpha1-antitrypsin level was normal. Antinuclear and anti-smith antibodies, rheumatoid factor, and cryoglobulins were negative. CT showed enlarged lymph nodes in the axillary and inguinal areas, bilateral small pleural effusion, moderate hepatosplenomegaly, severe fatty infiltration of the liver, and thickening of lower abdominal subcutaneous tissue. A liver biopsy showed steatohepatitis. Bone marrow aspirate and trephine were normal. A deep punch biopsy of a nodule from the right lower abdomen revealed lobular panniculitis with atypical lymphocytes and large macrophages with cytophagocytosis ("beanbag" cells) (Figures 3 and 4). Immunohistochemistry showed that these atypical cells were positive for CD3, CD8, granzyme B, and perforin, and negative for CD56. T-cell gene rearrangement studies on skin lesions revealed a monoclonal T-cell receptor (gamma-chain) gene rearrangement, supporting the diagnosis of subcutaneous panniculitis-like T-cell lymphoma. On presentation, the initial treatment included 6 U of fresh frozen plasma, 2 U of packed red blood cells, and 2 g IV fibrinogen for 3 consecutive days. The patient was started on prednisolone 60 mg orally once daily and cyclosporine A 5 mg/kg/d orally in two divided doses. The fever and other systemic symptoms and skin lesions resolved within 2 weeks after the treatment. The prednisolone dose was tapered gradually, and a maintenance dose of cyclosporine A was continued. The patient's condition remained in remission at 12-month follow-up; there was no evidence of clinical relapse.

The diagnostic importance of the normal finding.

When a diagnostic test is reported as normal, the clinician generally uses it only to rule out certain diseases. However, if properly interpreted, the normal value may help to differentiate among diagnoses that yield normal results with different frequencies. A simple method permits the extraction of such information. The physician estimates the probability of various diagnoses and then combines these estimates with the anticipated frequency of negative results for each disease under consideration.

The clinical significance of slightly to moderately increased liver transaminase values in asymptomatic patients.

Our aim was to study liver disorders in asymptomatic patients with slightly to moderately increased liver transaminase values in a population living in an area with a low prevalence of viral and hereditary liver diseases. One hundred and fifty consecutive patients with slightly to moderately increased liver transaminases for at least 6 months without symptoms or signs of liver disease were included. Median (range) was 0.75 microkat/l (0.24-2.9) for aspartate aminotransferase (ASAT) and 1.18 microkat/l (0.28-4.5) for alanine aminotransferase (ALAT). A percutaneous liver biopsy was performed, and blood was sampled for a detailed biochemical and serologic profile. Chronic viral hepatitis C was found in 15.3% of the patients, autoimmune hepatitis in 1.3%, primary biliary cirrhosis in 1.3%, and heterozygotic alpha-1-antitrypsin deficiency in 0.7%. Presumed alcoholic liver disease was diagnosed in 8%, and non-alcoholic steatohepatitis in 2%. Chronic hepatitis with no obvious etiology was diagnosed in 24%, of whom 39% had interface hepatitis (piecemeal activity). Seventy-one per cent of these 39% had measurable levels of autoantibodies, but IgG levels within normal limits prevented the 'clinical' diagnosis of autoimmune hepatitis. Liver steatosis was the diagnosis in 40%. Most were overweight and had increased serum triglyceride levels. However, in 13.3% the fatty infiltration was considered 'essential', as both body mass index (BMI) and triglyceride levels were normal. Other diagnoses were liver fibrosis with no obvious inflammatory activity (3.3%), cirrhosis of unknown etiology (0.7%), and for the remaining (3.3%) patients histopathologic findings were considered 'normal'. Cirrhosis was found in five biopsy specimens: hepatitis C (n = 2), autoimmune hepatitis (n = 1), primary biliary cirrhosis (n = 1), and cryptogenic cirrhosis (n = 1). No concomitant disease was of importance for the diagnosis and/or histopathologic findings. No obvious drug-related increased liver test results were found with any single drug. However, patients with chronic hepatitis of unknown etiology, especially with interface hepatitis, significantly more often than the rest of the population were receiving drug treatment. Most transaminitis patients had steatosis, and some had defined diseases including chronic hepatitis C. Chronic hepatitis of unknown etiology was found in a substantial proportion (24%) of a population living in an area with a low burden of hepatic viruses and genetic disorders.

InternalMed_Harrison

Differences between Screening Tests and Confirmatory Tests It is important to distinguish between clinical laboratory tests that can be used to screen for disease and those that offer a confirmatory result. Screening tests are generally less expensive and more widely available than are confirmatory tests, which often require more specialized equipment or personnel. As a general principle, screening tests are designed to identify all individuals who have the disease of interest, even if, in the process, some healthy individuals are misidentified as possibly having the disease. In other words, maximization of the diagnostic sensitivity of screening tests inevitably comes at the expense of reduced diagnostic specificity. Confirmatory testing is intended to correctly separate those individuals who have a disease from those who do not.

Non-alcoholic fatty liver disease

Blood tests that are useful to confirm diagnosis or rule out others include erythrocyte sedimentation rate, glucose, albumin, and kidney function. Because the liver is important for making proteins used in blood clotting, coagulation-related studies are often carried out, especially the INR (international normalized ratio). In people with fatty liver with associated inflammatory injury (steatohepatitis) blood tests are usually used to rule out viral hepatitis (hepatitis A, B, C and herpesviruses such as Epstein-Barr virus or cytomegalovirus), rubella, and autoimmune diseases. Low thyroid activity is more prevalent in people with NASH, which would be detected by determining the thyroid-stimulating hormone. Some biomarker-based blood tests have been developed and may be useful for diagnosis.

[What shall I do with a patient with elevated liver tests?].

In this article you will find a short reminder on the lab tests of the hepatic function and of the hepatic diseases. It shall help treat a patient with elevated liver tests. We will distinguish between an elevation of the liver enzymes of more/equal 5x and less than 5x the norm. An elevation of more/equal 5x the norm of the liver enzymes requires a rapid work-up. When the elevation is less than 5x the norm, one can proceed in two steps. A life style modification can be proposed after excluding a viral hepatitis and a hemochromatosis. If the liver enzymes still remind elevated, rarer causes must be searched.

InternalMed_Harrison

One of the most frequent reasons for performing clinical laboratory tests is to support, confirm, or refute a diagnosis of disease that is suspected on the basis of other information sources, such as history, physical examination findings, and imaging studies. The following questions need to be considered: Which clinical laboratory tests may be of value in supporting, confirming, or excluding the clinical impression? What is the most efficient test-ordering strategy? Will a positive test result confirm the clinical impression or even definitively establish the diagnosis? Will a negative result disprove the clinical suspicion, and, if so, what further testing or alternative approach will be needed? What are the known sources of false-positive and false-negative results, and how are these misleading results recognized?

Coeliac disease

If all these antibodies are negative, then anti-DGP antibodies (antibodies against deamidated gliadin peptides) should be determined. IgG class anti-DGP antibodies may be useful in people with IgA deficiency. In children younger than two years, anti-DGP antibodies perform better than anti-endomysial and anti-transglutaminase antibodies tests. Because of the major implications of a diagnosis of coeliac disease, professional guidelines recommend that a positive blood test is still followed by an endoscopy/gastroscopy and biopsy. A negative serology test may still be followed by a recommendation for endoscopy and duodenal biopsy if clinical suspicion remains high.

Evaluation of laboratory tests used in screening ambulatory patients.

Multiple other tests have been suggested for screening healthy patients. Hopefully, the above illustrations give a perspective with regards to the incidence of disease versus other causes that would lead to abnormal test results. The most frequent cause of an abnormal test result is physiologic variation, laboratory variation, or both. Even in laboratories with excellent quality assurance programs, the results falling outside the reference ranges most likely indicate physiologic variation, laboratory variation, or both. The physician will obtain more meaningful data from the laboratory when testing is ordered to confirm diagnostic suspicions that were raised during the history and physical examination of the patient. When a physician receives abnormal test results that were ordered as screening tests without any diagnostic suspicion, a search should be made for signs and symptoms that would correlate with that abnormal test. In the absence of any evidence that would indicate underlying disease, it would usually be unnecessary to pursue follow-up testing.

Glycogen Hepatopathy: A Reversible yet Relapsing Cause of Hepatitis in Type 1 Diabetics.

Glycogen hepatopathy (GH), a rare glycogen storage disease caused by genetic or acquired overactivation of hepatic glycogen synthesis enzymes, can mimic non-alcoholic fatty liver disease (NAFLD). We describe a case of biopsy-proven GH in an adult with type 1 diabetes mellitus (DM). A 33-year-old Honduran woman with a 25-year history of type 1 DM complicated by gastroparesis, multiple episodes of diabetic ketoacidosis (DKA) and hypoglycemia, and recurrent pancreatitis was referred for abnormal liver enzymes. Family history was negative for liver disease. There was no history of alcohol or recreational drug use. Patients' medications included insulin and thyroxine. Physical exam showed hepatomegaly but no stigmata of chronic liver disease. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) had ranged from 100's to over 7000 U/L while alkaline phosphatase (ALP) was elevated to over 400 IU/L. Albumin, total bilirubin, platelets, international normalized ratio (INR), eosinophils, viral hepatitis panel, antinuclear antibody (ANA), smooth muscle antibody (Ab), anti-liver-kidney microsomal (LKM) Ab, celiac serologies, ceruloplasmin, alpha 1 antitrypsin, iron studies, and acetaminophen levels were all normal. An abdominal ultrasound showed "fatty liver" and an atrophic pancreas. CT abdomen showed hepatomegaly. The common bile duct (CBD) was found to be normal on endoscopic ultrasound (EUS) and magnetic resonance cholangiopancreatography (MRCP). A liver biopsy was pursued eventually, demonstrating glycogenotic hepatocytes. GH is frequently misdiagnosed as NAFLD, a more common liver disease that occurs in association with diabetes While GH is known to be reversible, NAFLD has been known to progress to advanced liver disease, ranging from cirrhosis to hepatocellular carcinoma. Definite diagnosis often requires liver biopsy because of overlapping clinical and radiographical pictures. Elevation of both glucose and insulin levels in the setting of fragile DM control is thought to play a role via overstimulation of glycogen synthesis. Recommended treatment is stable "tight" glycemic control; pancreatic transplantation has resulted in sustained GH remission in two case reports. The required degree of stability and tightness of glucose control is not yet known. An increased awareness of GH is needed in an attempt to prevent delay in diagnosis, in a condition with an otherwise unknown incidence.

InternalMed_Harrison

As previously noted, the best way to increase the sensitivity and specificity of laboratory tests in the detection of liver disease is to employ a battery of tests that includes the aminotransferases, alkaline phosphatase, bilirubin, albumin, and prothrombin time along with the judicious use of the other tests described in this chapter. Table 358-1 shows how patterns of liver tests can lead the clinician to a category of disease that will direct further evaluation. However, it is important to remember that no single set of liver tests will necessarily provide a diagnosis. It is often necessary to repeat these tests on several occasions over days to weeks for a diagnostic pattern to emerge. Figure 358-1 is an algorithm for the evaluation of chronically abnormal liver tests.

Wilson's disease

Wilson's disease is a genetic disorder in which excess copper builds up in the body. Symptoms are typically related to the brain and liver. Liver-related symptoms include vomiting, weakness, fluid build up in the abdomen, swelling of the legs, yellowish skin and itchiness. Brain-related symptoms include tremors, muscle stiffness, trouble in speaking, personality changes, anxiety, and psychosis. Wilson's disease is caused by a mutation in the Wilson disease protein (ATP7B) gene. This protein transports excess copper into bile, where is excreted in waste products. The condition is autosomal recessive; for a person to be affected, they must inherit a mutated copy of the gene from both parents. Diagnosis may be difficult and often involves a combination of blood tests, urine tests and a liver biopsy. Genetic testing may be used to screen family members of those affected.

Risk preference and laboratory test selection.

The risk preferences in situations of potential gain, and of potential loss, expressed by 67 physicians were correlated with the numbers of laboratory tests they selected after review of identical copies of two outpatient charts. Physicians who chose a 50/50 gamble of losing ten or no years of life expectancy over an equivalent certain loss of five years selected twice as many tests as those who chose the loss (p less than 0.025). Risk preferences may provide some insight into why some physicians order more laboratory tests than do others.

Atomic Absorption Spectrometry in Wilson's Disease and Its Comparison with Other Laboratory Tests and Paraclinical Findings.

Wilson's disease (WD) is an autosomal recessive disease with genetic abnormality on chromosome 13 causing defect in copper metabolism and increased copper concentration in liver, central nervous system and other organs, which causes different clinical manifestations. The aim of this study was to determine the sensitivity of different clinical and paraclinical tests for diagnosis of Wilson's disease. Paraffin blocks of liver biopsy from 41 children suspicious of WD were collected. Hepatic copper concentrations were examined with atomic absorption spectrophotometry (Australian GBC, model: PAL 3000). Fifteen specimens had hepatic copper concentration (dry weight) more than 250μg/g. Clinical and laboratory data and histologic slides of liver biopsies of these 15 children were reviewed retrospectively. Liver tissue was examined for staging and grading of hepatic involvement and also stained with rubeonic acid method for copper. Patients were 5-15 years old (mean age=9.3 years, standard deviation=2.6) with slight male predominance (9/15=60%). Five (33%) patients were 10 years old. Three (20%) of them were referred for icterus, 8 (54%) because of positive family history, 2 (13%) due to abdominal pain and 2 (13%) because of hepatosplenomegaly and ascites. Serum AST and ALT levels were elevated at the time of presentation in all patients. In liver biopsy, histological grade and stage was 0-8 and 0-6 respectively, 2 (13%) had cirrhosis, 1 (7%) had normal biopsy and 12 (80%) showed chronic hepatitis. Hepatic copper concentrations were between 250 and 1595 μg/g dry weight. The sensitivity of various tests were 85% for serum copper, 83% for serum ceruloplasmin, 53% for urinary copper excretion, 44% for presence of KF ring and 40% for rubeonic acid staining on liver biopsies. None of the tests stated in the article were highly sensitive for diagnosis of WD, so we suggest that diagnosis should be based on combination of family history, physical examination and different tests.

Realistic expectations of laboratory testing.

The ordering, reviewing, and interpreting of laboratory tests require recognition and familiarity with the concepts of normal values, sensitivity, specificity, predictive values, and prevalence. The significance of these test properties in clinical decision-making is explained.


They describe pleural fluid parameters of transudate, so if the patient is not in heart failure it is a hydropic decompensation. No other studies are needed.

In a patient with liver cirrhosis and ascites, who develops a pleural effusion with the following data in the pleural fluid: LDH 45 U/L (serum 220 U/L), pleural/serum protein ratio 0.3 and pleural/serum LDH ratio 0.2. What would be the appropriate attitude?

The study of the fluid with cell count, glucose, pH, ADA, cholesterol and culture should be extended. ADA, cholesterol and culture.

Empirical antibiotherapy for suspected parapneumonic effusion.

Continue treatment of his liver disease.

Evaluation of pleural fluid in patients with cirrhosis.

Although fluid analysis usually is the first step toward identifying the cause of pleural effusion in patients with cirrhosis and ascites, there are no available data on the reliability of this approach, therefore, we retrospectively evaluated hematologic and biochemical parameters from pleural fluid analysis in 21 patients with hepatic hydrothorax (with proven peritoneal-pleural communication) and 6 patients with primary pleural disease (2 with tuberculosis, 3 with parapneumonic effusion, and 1 with empyema). The criteria developed by Light were diagnostic of pleural "exudate" in only one of six patients with primary pleural disease, concentrations of leukocytes, total protein (TP), albumin, and lactic dehydrogenase (LDH) in both fluids were measured and pleural fluid-to-ascites ratios of these measurements were calculated. Only ratio values for leukocytes and TP were higher in the group of patients with primary pleural disease compared with those with hepatic hydrothorax. Ratio values for leukocytes and TP overlapped between both groups during baseline conditions and during episodes of spontaneous bacterial peritonitis and pleuritis. We conclude that pleural fluid analysis has limited diagnostic efficacy in the patient with cirrhosis. Data collected by other methods--clinical and radiologic--should assist in arriving at the correct diagnosis.

Parapneumonic effusion

A parapneumonic effusion is a type of pleural effusion that arises as a result of a pneumonia, lung abscess, or bronchiectasis. There are three types of parapneumonic effusions: uncomplicated effusions, complicated effusions, and empyema. Uncomplicated effusions generally respond well to appropriate antibiotic treatment. Diagnosis The criteria for a complicated parapneumonic effusion include Gram stain–positive or culture-positive pleural fluid, pleural fluid pH <7.20, and pleural fluid LDH that is greater than three times the upper limit of normal of serum LDH. Diagnostic techniques available include plain film chest x-ray, computed tomography (CT), and ultrasound. Ultrasound can be useful in differentiating between empyema and other transudative and exudative effusions due in part to relative echogenicity of different organs such as the liver (often isoechogenic with empyema).

Hepatic hydrothorax

The most noticeable symptoms are usually those of cirrhosis and portal hypertension. Most people have signs of end-stage liver disease. pleuroperitoneal communications. The main method of diagnosis is extracting the fluid via thoracentesis. After this, the fluid is analyzed for diagnosis and to help rule out other possible causes like infection or cancer. The fluid can be analyzed for serum, protein, albumin, lactate dehydrogenase, and cell count. The fluid is a transudate and similar to fluid found in ascites. There may be a higher protein and albumin content in hepatic hydrothorax due to the pleura absorbing the water. To rule out heart-related causes of pleural effusion, an echocardiogram can be performed. Pleuroperitoneal communications are best detected by peritoneal scintigraphy. In this procedure, radioactive tracer is injected via needle into ascitic fluid, a procedure known as paracentesis. After that, a gamma camera is used to take images, showing the tracer in the pleural

Pleural effusion

The ratio of pleural fluid protein to serum protein is greater than 0.5 The ratio of pleural fluid LDH and serum LDH is greater than 0.6 Pleural fluid LDH is greater than 0.6 or times the normal upper limit for serum. Different laboratories have different values for the upper limit of serum LDH, but examples include 200 and 300 IU/l.

Pleural cavity

If malignant cells are present, a pathologist may perform additional studies including immunohistochemistry to determine the etiology of the malignancy. Chemical analysis Chemistry studies may be performed including pH, pleural fluid:serum protein ratio, LDH ratio, specific gravity, cholesterol and bilirubin levels. These studies may help clarify the etiology of a pleural effusion (exudative vs transudative). Amylase may be elevated in pleural effusions related to gastric/esophageal perforations, pancreatitis or malignancy. Pleural effusions are classified as exudative (high protein) or transudative (low protein).

Thoracentesis

The use of ultrasound for needle guidance can minimize the complication rate. Follow-up imaging While chest X-ray has traditionally been performed to assess for pneumothorax following the procedure, it may no longer be necessary to do so in asymptomatic, non-ventilated persons given the widespread use of ultrasound to guide this procedure. Interpretation of pleural fluid analysis Several diagnostic tools are available to determine the etiology of pleural fluid. Transudate versus exudate First the fluid is either transudate or exudate. A transudate is defined as pleural fluid to serum total protein ratio of less than 0.5, pleural fluid to serum LDH ratio > 0.6, and absolute pleural fluid LDH > 200 IU or > 2/3 of the normal.

[Cuttoff values of biochemical tests on pleural fluid: their usefulness in differential diagnosis of 1,040 patients with pleural effusion].

The aim of biochemical pleural fluid testing is to reach an etiological diagnosis of the pleural effusion. We assessed the utility of considering cuttoff points for the wide range of analytes used to investigate pleural fluid. Among 1,040 patients with pleural effusion, we sought the etiologies of those fluids which showed any of the following characteristics: red blood cell count = 10 x 109/L, leukocytes = 10 x 109/L, percentage of neutrophils or lymphocytes >50%, protein = 50 g/L, glucose = 60 mg/dL, pH = 7.2, lactate dehydrogenase = 1,000 U/L, adenosine deaminase = 40 U/L, amylase = 100 U/L or cholesterol = 60 mg/dL. Some of the more prominent findings were: a) a sixth of transudates were blood-tinged or contained predominantly neutrophils; b) a groosly bloody fluid suggests malignant disease, trauma, or pulmonary embolization; c) nearly 90% of fluids containing = 10 x 10(9) leukocytes/L were parapneumonics; d) 73% of tuberculous pleural fluids had protein > or = 50 g/L, e) tuberculosis and parapneumonics explained more than 90% of fluids with high adenosine deaminase content; f) one third of amylase-rich pleural effusions were malignant; g) a low pleural glucose or pH levels indicate that patient probably has a parapneumonic, tuberculous or malignant etiology; y h) the diagnostic yield of pleural fluid cytology in malignant effusions was 57%, a percentage which raised to 94% in those with low glucose fluid level. Cuttof values of biochemical pleural fluid tests may greatly support particular causes of pleural effusions.

Pleural effusion

When a pleural effusion has been determined to be exudative, additional evaluation is needed to determine its cause, and amylase, glucose, pH and cell counts should be measured. Red blood cell counts are elevated in cases of bloody effusions (for example after heart surgery or hemothorax from incomplete evacuation of blood). Amylase levels are elevated in cases of esophageal rupture, pancreatic pleural effusion, or cancer. Glucose is decreased with cancer, bacterial infections, or rheumatoid pleuritis. pH is low in empyema (<7.2) and maybe low in cancer. If cancer is suspected, the pleural fluid is sent for cytology. If cytology is negative, and cancer is still suspected, either a thoracoscopy, or needle biopsy of the pleura may be performed. Gram staining and culture should also be done.

Thoracentesis

Transudate Congestive heart failure Nephrotic syndrome Hypoalbuminemia Cirrhosis Atelectasis trapped lung Peritoneal dialysis Superior vena cava obstruction Amylase A high amylase level (twice the serum level or the absolute value is greater than 160 Somogy units) in the pleural fluid is indicative of either acute or chronic pancreatitis, pancreatic pseudocyst that has dissected or ruptured into the pleural space, cancer or esophageal rupture. Glucose This is considered low if pleural fluid value is less than 50% of normal serum value. The differential diagnosis for this is: rheumatoid effusion. The levels are characteristically low (<15 mg/dL). lupus effusion bacterial empyema malignancy tuberculosis esophageal rupture (Boerhaave syndrome) pH Normal pleural fluid pH is approximately 7.60. A pleural fluid pH below 7.30 with normal arterial blood pH has the same differential diagnosis as low pleural fluid glucose.

Thoracentesis

A transudate is defined as pleural fluid to serum total protein ratio of less than 0.5, pleural fluid to serum LDH ratio > 0.6, and absolute pleural fluid LDH > 200 IU or > 2/3 of the normal. An exudate is defined as pleural fluid that filters from the circulatory system into lesions or areas of inflammation. Its composition varies but generally includes water and the dissolved solutes of the main circulatory fluid such as blood. In the case of blood it will contain some or all plasma proteins, white blood cells, platelets and (in the case of local vascular damage) red blood cells. Exudate hemorrhage Infection Inflammation Malignancy Iatrogenic Connective tissue disease Endocrine disorders Lymphatic disorders vs Constrictive pericarditis Transudate Congestive heart failure Nephrotic syndrome Hypoalbuminemia Cirrhosis Atelectasis trapped lung Peritoneal dialysis Superior vena cava obstruction

Management of pleural effusions.

This review summarizes current strategies in the treatment of patients with pleural effusion. To determine whether a patient has a transudative or exudative pleural effusion, Light's criteria should be applied to measure the concentrations of protein and lactate dehydrogenase (LDH) in the pleural fluid and serum. If the effusion is transudative, therapy should be directed toward the underlying congestive heart failure, cirrhosis, or nephrosis. Consideration should be given to pleurodesis with a sclerosant if patients with recurrent transudative effusion have severe dyspnea due to their effusion. If the effusion is exudative, attempts should be made to define the etiology. The diagnosis of pleural malignancy is most easily established via pleural fluid cytology. If this is negative and the patient is suspected of having pleural malignancy, thoracoscopy is indicated. The concentrations of adenosine deaminase and gamma-interferon in pleural fluid are useful in the diagnosis of pleural tuberculosis. Patients with pneumonia and pleural effusion should undergo therapeutic thoracentesis; the pleural fluid should be Gram-stained and cultured, and the differential cell count, glucose and LDH concentration, and pH should be determined. Indicators of a poor prognosis include the presence of frank pus, a positive Gram-stain, a pleural glucose concentration of less than 2.2 mmol/L, a pH less than 7.00, the presence of pleural loculations, and an LDH concentration greater than three times the upper limit of normal in serum. If the pleural fluid cannot be completely evacuated because of loculations, intrapleural thrombolytic therapy should be considered. If thrombolytics are ineffective, thoracoscopy or thoracotomy with decortication should be performed. Dyspneic patients with malignant pleural effusions whose dyspnea is relieved with therapeutic thoracentesis should be considered for pleurodesis using a tetracycline derivative. Talc is not recommended because it induces acute respiratory distress syndrome in about 5% of patients, with an overall mortality of 1%.

InternalMed_Harrison

288 be measured. In contrast to “spontaneous” bacterial peritonitis, which may complicate cirrhotic ascites (see “Complications,” below), secondary peritonitis is suggested by an ascitic glucose level <50 mg/dL, an ascitic LDH level higher than the serum LDH level, and the detection of multiple pathogens on ascitic fluid culture. When pancreatic ascites is suspected, the ascitic amylase level should be measured and is typically >1000 mg/dL. Cytology can be useful in the diagnosis of peritoneal carcinomatosis. At least 50 mL of fluid should be obtained and sent for immediate processing. Tuberculous peritonitis is typically associated with ascitic fluid lymphocytosis but can be difficult to diagnose by paracentesis. A smear for acid-fast bacilli has a diagnostic sensitivity of only 0 to 3%; a culture increases the sensitivity to 35–50%. In patients without cirrhosis, an elevated ascitic adenosine deaminase level has a sensitivity of >90% when a cut-off value of 30–45 U/L is used. When

Pleural empyema

The most often used "golden" criteria for empyema are pleural effusion with macroscopic presence of pus, a positive Gram stain or culture of pleural fluid, or a pleural fluid pH under 7.2 with normal peripheral blood pH. Clinical guidelines for adult patients therefore advocate diagnostic pleural fluid aspiration in patients with pleural effusion in association with sepsis or pneumonic illness. Because pleural effusion in the pediatric population is almost always parapneumonic and the need for chest tube drainage can be made on clinical grounds, British guidelines for the management of pleural infection in children do not recommend diagnostic pleural fluid sampling.

Lactate dehydrogenase

Testing in other body fluids Exudates and transudates Measuring LDH in fluid aspirated from a pleural effusion (or pericardial effusion) can help in the distinction between exudates (actively secreted fluid, e.g., due to inflammation) or transudates (passively secreted fluid, due to a high hydrostatic pressure or a low oncotic pressure). The usual criterion (included in Light's criteria) is that a ratio of fluid LDH versus upper limit of normal serum LDH of more than 0.6 or indicates an exudate, while a ratio of less indicates a transudate. Different laboratories have different values for the upper limit of serum LDH, but examples include 200 and 300 IU/L. In empyema, the LDH levels, in general, will exceed 1000 IU/L. Meningitis and encephalitis High levels of lactate dehydrogenase in cerebrospinal fluid are often associated with bacterial meningitis. In the case of viral meningitis, high LDH, in general, indicates the presence of encephalitis and poor prognosis.

Hepatic hydrothorax

There are no specific symptoms, because it generally occurs with ascites and other manifestations of increased pressure in the portal vein caused by liver disease. Pleural fluid can far more easily cause symptoms than ascitic fluid, due to the lower volume of the pleural cavity as compared to the abdominal cavity. The main symptoms are usually related to the symptoms of liver cirrhosis and ascites. Less often, it may be the only manifestation of chronic liver disease. The symptoms depend on many factors, such as the effusion's volume, rate of accumulation, and the co-existence of cardiopulmonary disease. The disease may cause no symptoms and be incidentally detected by medical scans, or it may cause large pleural effusions that result in respiratory symptoms like cough, shortness of breath, low blood oxygen, and respiratory failure. Most people have progressive difficulty breathing and reduced tolerance for exercise. Rarely, there may be acute cases that accumulate fluid rapidly and

Hepatic hydrothorax

Hepatic hydrothorax is a rare form of pleural effusion that occurs in people with liver cirrhosis. It is defined as an effusion of over 500 mL in people with liver cirrhosis that is not caused by heart, lung, or pleural disease. It is found in 5-10% of people with liver cirrhosis and 2-3% of people with pleural effusions. It is much more common on the right side, with 85% of cases occurring on the right, 13% on the left, and 2% in both. Although it is most common in people with severe ascites, cases have been reported where people only had mild or no ascites. Symptoms are not specific, and mostly involve the respiratory system.

Thoracentesis

pH Normal pleural fluid pH is approximately 7.60. A pleural fluid pH below 7.30 with normal arterial blood pH has the same differential diagnosis as low pleural fluid glucose. Triglyceride and cholesterol Chylothorax (fluid from lymph vessels leaking into the pleural cavity) may be identified by determining triglyceride and cholesterol levels, which are relatively high in lymph. A triglyceride level over 110 mg/dl and the presence of chylomicrons indicate a chylous effusion. The appearance is generally milky but can be serous. The main cause for chylothorax is rupture of the thoracic duct, most frequently as a result of trauma or malignancy (such as lymphoma). Cell count and differential The number of white blood cells can give an indication of infection. The specific subtypes can also give clues as to the type on infection. The amount of red blood cells are an obvious sign of bleeding.

Urinothorax

Diagnosis Due to the main symptoms typically being urological rather than respiratory, the condition requires exclusion of other conditions and the identification of specific symptoms before diagnosis. Pleural fluid analysis is one way to diagnose the condition. The pleural fluid is most often straw-colored, and it has a distinct smell like ammonia. The fluid usually has a nucleated cell count between 50 and 1500 per cm3. The pH of the fluid is usually between 5 and 7. Primary factors for diagnosing urinothorax by pleural fluid include low protein and high lactate dehydrogenase content. Low glucose levels and acidity are also described, but are not reliable ways to diagnose or rule out urinothorax. The most important chemical diagnostic factor of the fluid is that the ratio of creatinine to serum is more than 1 and usually more than 10.

InternalMed_Harrison

Perform diagnostic thoracentesis Measure pleural fluid protein and LDH Exudate Further diagnostic procedures Transudate Treat CHF, cirrhosis, nephrosis Measure PF glucose Obtain PF cytology Obtain differential cell count Culture, stain PF PF marker for TB Consider:Malignancy Bacterial infections Rheumatoid pleuritis Glucose < 60 mg/dL No diagnosis Consider pulmonary embolus (spiral CT or lung scan) Treat for PE Treat for TB PF marker for TB Observe Consider thoracoscopy or image-guided pleural biopsy Any of following met? PF/serum protein > 0.5 PF/serum LDH > 0.6 PF LDH > 2/3 upper normal serum limit Pleural effusion Yes No Yes Yes Yes No No No SYMPTOMS IMPROVING FIGURE 316-1 Approach to the diagnosis of pleural effusions. CHF, congestive heart failure; CT, computed tomography; LDH, lactate dehydrogenase; PE, pulmonary embolism; PF, pleural fluid; TB, tuberculosis.

Ascites -- Evaluation

Additional tests may be performed only if a specific diagnosis is suspected clinically. LDH and glucose level should be determined in suspected cases of secondary peritonitis. Other tests to consider include amylase (greater than 1000 U/L suggests pancreatic ascites). Mycobacterial culture should be performed only if tuberculosis is strongly suspected. Other ascitic fluid indices such as lactate and pH offer little to no additional information. Chest x-ray may reveal elevated diaphragm.

Pleural effusion

Transudative pleural effusions are defined as effusions that are caused by systemic factors that alter the pleural equilibrium, or Starling forces. The components of the Starling forces – hydrostatic pressure, permeability, and oncotic pressure (effective pressure due to the composition of the pleural fluid and blood) – are altered in many diseases, e.g., left ventricular failure, kidney failure, liver failure, and cirrhosis. Exudative pleural effusions, by contrast, are caused by alterations in local factors that influence the formation and absorption of pleural fluid (e.g., bacterial pneumonia, cancer, pulmonary embolism, and viral infection). An accurate diagnosis of the cause of the effusion, transudate versus exudate, relies on a comparison of the chemistries in the pleural fluid to those in the blood, using Light's criteria. According to Light's criteria (Light, et al. 1972), a pleural effusion is likely exudative if at least one of the following exists:

The value of ascitic fluid polymorphonuclear cell count determination during therapy of spontaneous bacterial peritonitis in patients with liver cirrhosis.

Spontaneous bacterial peritonitis is one of the most common complications attending the onset of ascites in patients with liver cirrhosis. The aim of this study was to demonstrate whether it is possible, on the basis of ascitic fluid polymorphonuclear cell count in patients with liver cirrhosis and spontaneous bacterial peritonitis, to determine the optimal duration of cefotaxime therapy, as the most frequently applied empirical therapy, and possibly anticipate the disease recurrence. In 16 patients with alcoholic liver cirrhosis and confirmed diagnosis of spontaneous bacterial peritonitis, cefotaxime therapy was administered 2g t.i.d. during 5 days. Before the therapy, at 48 hours, 5 days and 15-20 days after the cefotaxime therapy was started, in all patients with spontaneous bacterial peritonitis diagnostic abdominal paracentesis was performed, each time determining the ascitic fluid polymorphonuclear cell count together with microbiological analysis. In the course of the "primary" spontaneous bacterial peritonitis attack, 3 patients died (18.8%). In 4 patients the recurrence of spontaneous bacterial peritonitis was observed within 15-20 days after therapy was discontinued. Two patients died during the therapy of spontaneous bacterial peritonitis recurrence. After 48 hours of therapy, 11 patients with the "primary" spontaneous bacterial peritonitis attack were without any symptoms (68.8%). Out of these 11, 10 patients (62.5%) had the ascitic fluid polymorphonuclear cell count lower than 250/mm3. After 5 days of therapy, 12 patients (75%) were free of symptoms, and the number of ascitic fluid polymorphonuclear cell count < 250/mm3 was still found in 10 (62.5%) patients. No association between the presence of symptoms 48 hours after the therapy and the recurrence of spontaneous bacterial peritonitis was established. A significant association was found between the ascitic fluid polymorphonuclear cell count determined 48 hours after the therapy and the recurrence of spontaneous bacterial peritonitis. A recurrence occurred in only 1 patient with the number of ascitic fluid polymorphonuclear cell count < 250/mm3, 48 hours after the therapy was started. A recurrence of spontaneous bacterial peritonitis occurred in all the patients who had an ascitic fluid PMN cell count > or = 250/mm3, 48 hours after the therapy was started. By monitoring the ascitic fluid PMN cell count it seems to be possible to determine the efficacy and optimal duration of cefotaxime therapy in patients with spontaneous bacterial peritonitis when it is of most importance that the number of ascitic fluid PMN cell count should decrease below 250/mm3 during the therapy.

The clinical value of ascitic fluid culture and leukocyte count studies in alcoholic cirrhosis.

Because of the paucity of studies establishing the accepted leukocyte count is sterile ascites, less than 300 WBC per mm3 with 25% polymorphonuclear (PMN) leukocytes, peritoneal fluid WBC counts and bacterial cultures were studied in 63 consecutive hospitalized patients with alcoholic cirrhosis and ascities. In 58 culture-negative patients the ascitic fluid WBC count range was 28 to 1800 and 50% of counts were greater than 300 WBC per mm3. The percentage of PMN leukocytes ranged from 2 to 98%. Five patients with spontaneous bacterial peritonitis (SBP), proven by positive cultures, had an ascitic WBC count range of 300 to 6320 WBC per mm3 and a PMN leukocyte range of 20 to 76%. Physical findings did not allow clear separation of the two groups. Anaerobic organisms were not found. It is concluded: (1) differentiation of SBP from sterile ascities relies on prompt ascitic fluid bacteriology; (2) the improved survival of 40% of SBP patients in this study may be related to an increased awareness of the entity and early treatment.

Diagnosing ascitic etiology on a biochemical basis.

The analysis of ascitic fluid has been complicated by several new tests. To simplify its assessment, we evaluated ascitic fluid pH with six other parameters prospectively and simultaneously in blood and ascitic fluid in sixty patients with ascites. Sixty patients were selected on whom abdominal paracentesis was performed in order to determine which tests were the most reliable for the etiological diagnosis of ascites. Their ascitic fluid pH, cholesterol, albumin, and total proteins were analyzed to distinguish between malignant and cirrhotic ascites. The diagnosis of cirrhosis was based on histological findings, and/or clinical, biochemical, and endoscopic/ultrasonographic findings in whom percutaneous liver biopsy was contraindicated. The serum-ascites albumin gradient was higher (p<0.001) in cirrhotic as compared to tubercular, malignant or cardiac ascites. We discovered that ascitic fluid lactate dehydrogenase and cholesterol were best for diagnosing malignant ascites, ascitic fluid glucose and ascitic fluid/blood glucose ratio were perfect for diagnosing tubercular ascites, and ascitic fluid pH and lactate dehydrogenase were suitable for diagnosing spontaneous bacterial peritonitis. Correspondingly, ascitic fluid albumin, ascitic fluid/serum albumin, total proteins, and serum ascites albumin gradient were best for diagnosing sterile cirrhotic ascites. Diagnostic paracentesis is a useful procedure. The practice of ordering a battery of tests on every ascitic fluid specimen should be abandoned. Rather, an algorithm approach should be adopted in which the results of initial analysis guide us to further relent tests that help in arriving at the etiology of ascites.

The pH of ascitic fluid in the diagnosis of spontaneous bacterial peritonitis in alcoholic cirrhosis.

Fifty-six patients with alcoholic cirrhosis and ascites were studied. The ascitic fluid was analyzed for pH, PO2, PCO2 glucose, protein, specific gravity, amylase, lactic dehydrogenase, white blood cell count, polymorphonuclear count, and cytology. It was also cultured aerobically and anaerobically. Simultaneously, arterial blood was analyzed for pH, PO2, and PCO2. Venous blood was analyzed for complete blood count, protein, aspartate transaminase, and it was also cultured under aerobic and anaerobic conditions. Six patients had spontaneous bacterial peritonitis (SBP), i.e., culture was positive for Escherichia coli in five and Streptococcus faecalis in one. The mean (+/- S.E.) ascitic fluid pH in the SBP group wa 7.25 +/- 0.06 with a range of 7.12 to 7.31, while the ascitic fluid pH in the group with sterile ascites was 7.47 +/- 0.07 with a range of 7.39 to 7.58. The pH of the blood in both groups was 7.47 +/- 0.03. The pH of the ascites in the SBP group was significantly different from the pH in the group with sterile ascites, p less than 0.001. It was also significantly different from the blood pH, p less than 0.001. Highly significant inverse correlations existed between the ascitic pH in the SBP group and the ascitic white blood cell count (r = 0.84, p less than 0.01) and between the ascite pH in the SBP group and the ascitic polymorphonuclear count (r = -0.87 ,p less than 0.01). The ascitic fluid pH is recommended as an easy, quick, sensitive, and specific means of diagnosing SBP and it overcomes the problem of the present SBP diagnostic methods of utilizing an absolute white blood cell count greater than 500 per mm3 or a polymorphonuclear count greater than 250 per mm3 in which false positive interpretations occur.

Characteristics of pleural effusion with a high adenosine deaminase level: a case-control study.

Increased pleural fluid adenosine deaminase (ADA) is useful for diagnosing tuberculous pleurisy (TB), but high ADA levels are associated with other diseases. In this study, we compare various disease characteristics in patients with high-ADA pleural effusion. We retrospectively collected data for 456 patients with pleural fluid ADA levels of ≥ 40 U/L from January 2012 to October 2021. Cases were classified as TB (n = 203), pleural infection (n = 112), malignant pleural effusion (n = 63), nontuberculous mycobacteria (n = 22), malignant lymphoma (ML) (n = 18), autoimmune diseases (n = 11), and other diseases (n = 27), and data were compared among those diseases. Predictive factors were identified by comparing data for a target disease to those for all other diseases. A diagnostic flowchart for TB was developed based on those factors. The most frequent disease was TB, though 60.0% of patients were diagnosed with other diseases. Median ADA levels in patients with TB were 83.1 U/L (interquartile range [IQR] 67.2-104.1), higher than those of patients with pleural infection (median 60.9 [IQR 45.3-108.0], p = 0.004), malignant pleural effusion (median 54.1 [IQR 44.8-66.7], p < 0.001), or autoimmune diseases (median 48.5 [IQR 45.9-58.2], p = 0.008), with no significant difference from NTM (p = 1.000) or ML (p = 1.000). Pleural fluid lactate dehydrogenase (LDH) levels of < 825 IU/L were beneficial for the diagnosis of TB. Neutrophil predominance or cell degeneration, white blood cell count of ≥ 9200/µL or C-reactive protein levels of ≥ 12 mg/dL helped in diagnosing pleural infection. Pleural fluid amylase levels of ≥ 75 U/L and a pleural fluid ADA/total protein (TP) ratio of < 14 helped in diagnosing malignant pleural effusion. High serum LDH and high serum/pleural fluid eosinophils helped in diagnosing ML and autoimmune diseases, respectively. The flowchart was comprised of the following three factors: pleural fluid LDH < 825 IU/L, pleural fluid ADA/TP of < 14, and neutrophil predominance or cell degeneration, which were decided by a decision tree. The diagnostic accuracy rate, sensitivity, and specificity for the diagnosis of TB were 80.9%, 78.8%, and 82.6%, respectively. Cases involving high pleural fluid ADA levels should be investigated using several factors to distinguish TB from other diseases.

Frequency of microbial spectrum of spontaneous bacterial peritonitis in established cirrhosis liver.

Spontaneous bacterial peritonitis is one of the most frequent and serious complication in patients with liver cirrhosis and ascites associated with high mortality. Empiric antibiotic therapy should be initiated before the results of ascitic fluid cultures are available, guided by knowledge of the microbial spectrum of spontaneous bacterial peritonitis in a particular population. This is a descriptive study which was carried out in the Department of Gastroenterology and Hepatology, Postgraduate Medical Institute Hayatabad Medical Complex, Peshawar from January 2007 to December 2007. Fifty consecutive patients of established cirrhosis liver with ascites presenting with suspicion and or risk factors for spontaneous bacterial peritonitis were included in the study after informed consent. All selected patients were subjected to ascitic fluid tap. Twenty ml of ascitic fluid was aspirated in a heparinised disposable syringe; out of it 10 ml was immediately inoculated into blood culture bottle at bedside and sent for bacterial culture along with the remaining 10 ml for routine biochemical and cytological examination. Out of 50 patients, 28 (56%) were diagnosed to have spontaneous bacterial peritonitis or its variants. Classic spontaneous bacterial peritonitis was present in 11 patients (39.28%), 16 (57.14%) patients were found to have culture negative neutrocytic ascites and one patient (3.57%) had bacterascites. Out of 28 cases of spontaneous bacterial peritonitis 12 samples of ascitic fluid showed positive culture reports. E. coli was the most frequently cultured organism isolated in 8 (66.66%) cases, Streptococcus pneumonae in 2 patients (16.66%), S taphylococcus aurus and Klebsiella each in 1 case (8.33%). Spontaneous bacterial peritonitis and its variants is a common complication of liver cirrhosis with ascites. E. coli is the most frequent offending organism in these cases. Knowledge of the microbial spectrum of spontaneous bacterial peritonitis in a particular population is important for the selection of the most appropriate empiric antibiotic regimen.

Immediate diagnostic criteria for bacterial infection of ascitic fluid. Evaluation of ascitic fluid polymorphonuclear leukocyte count, pH, and lactate concentration, alone and in combination.

We prospectively evaluated the ascitic fluid (AF) polymorphonuclear cell (PMN) count, pH, and lactate concentration in single ascitic fluids from 60 patients to determine their relative predictive values for the immediate diagnosis of ascitic fluid infection. Nine of the 60 ascitic fluids were malignant. Of the remaining 51 samples, nine from cirrhotic patients were infected. The mean AF pH, lactate concentration, and PMN count in the infected group were 7.20 +/- 0.19, 80 +/- 51 mg/dl, and 18,199 +/- 19,650 cells/mm3, respectively, and all were significantly different from the corresponding values in noninfected ascites. Mean arterial blood-ascitic fluid (B-AF) pH and lactate gradients in the infected group were 0.23 +/- 0.17 and -46 +/- 31 mg/dl, respectively, and were significantly different from the corresponding values in noninfected ascites (p less than 0.05). Significant differences were not found between infected and malignant ascites, except for the AF PMN count (p less than 0.001). In cirrhosis with ascites, an AF pH less than or equal to 7.34 was the most specific single test (100%) and had the highest diagnostic accuracy (98%). In the larger group of patients with ascites of diverse etiology, a B-AF pH gradient greater than or equal to 0.10 or an AF PMN count greater than or equal to 500 cells/mm3 were the single tests with the highest diagnostic accuracy (92%). Combining an AF PMN count greater than 500 cells/mm3 with any of the other diagnostic criteria increased the specificity and diagnostic accuracy (up to 98%) compared to the best single criterion. Although our data support the use of a number of different combinations of AF measurements for the immediate diagnosis of infection, the simplest and most readily obtainable measurements are the pH and PMN count. Therefore, in the clinical setting we recommend the use of either an AF pH less than or equal to 7.34 or a B-AF pH gradient greater than or equal to 0.10 in combination with an AF PMN count greater than 500 cells/mm3 to obtain the highest degree of accuracy in the immediate diagnosis of ascitic fluid infection.

Analysis of ascitic fluid in cirrhosis.

In order to determine the composition of "normal" ascitic fluid, the results of analysis of the first paracentesis on 347 consecutive cirrhotic patients with ascites at the West Haven Veterans Administration Hospital between 1955 and 1976 were examined. The ascites was considered "normal" in 259 patients. Bacterial peritonitis was present in 51, malignant ascites in 18, pancreatitic ascites in 15, and ascites of other types in 4 patients. Normal ascites is sterile, usually clear, and contains 281 +/- 25 leukocytes/mm3 (mean +/- SEM), 27 +/- 2% of which are polymorphonuclear. In spontaneous bacterial peritonitis the fluid is usually cloudy, contains 6084 +/- 858 white blood cells/mm3, 77 +/- 4% of which were PMN and culture is positive for a single bacterial species, usually enteric in origin. Malignant and pancreatitis ascites are sterile, often cloudy, and contain an average of 696 +/- 273 and 1821 +/- 833 leukocytes/mm3, respectively, about half of which are polymorphonuclear. Amylase activity is increased in pancreatitic ascites, but not in other types of ascites. Stained smears of sediment for bacteria are often positive in bacterial peritonitis, but not in the other categories. Neither the specific gravity, protein concentration, nor glucose level is useful in the differential diagnosis of ascites. Based on the critical number of leukocytes alone, (500/mm3), one can accurately differentiate infected from uninfected fluid in over 90% of ascitic patients.

The diagnosis of bacterial peritonitis: comparison of pH, lactate concentration and leukocyte count.

It has been suggested that the hydrogen ion and lactate concentrations may be superior to the polymorphonuclear cell count (PMN) in ascitic fluid, in the diagnosis of bacterial peritonitis (BP). In order to compare the diagnostic accuracy of ascitic fluid measurements of pH, lactate, glucose and the PMN in BP, we analyzed the ascitic fluids of 70 consecutive patients in whom pH, lactate, glucose and the PMN count were measured in ascitic fluid and arterial blood. Fifty-one were cirrhotic patients with uninfected ascites, 14 had BP, one tuberculous peritonitis, two ascites secondary to peritoneal metastases and two with neoplastic liver involvement but without peritoneal metastases. Statistically, highly significant differences between patients with uninfected ascitic fluid and BP were observed for ascitic fluid PMN (122 vs. 2,686 per cu mm), ascitic fluid pH (7.45 vs. 7.24), arterial-ascitic fluid pH gradient (0.02 vs. 0.22), arterial lactate (12 vs. 25 mg per dl), ascitic fluid lactate (15 vs. 45 mg per dl) and arterial-ascitic fluid lactate gradient (-3 vs. -20 mg per dl). The most reliable diagnostic cutoff levels were determined for each of the parameters: PMN greater than 500 per cu mm; ascitic fluid pH less than 7.35; arterial-ascitic fluid pH gradient greater than 0.10; ascitic fluid lactate greater than 25 mg per dl; arterial-ascitic fluid lactate gradient less than -20 mg per dl; ascitic fluid glucose less than 60 mg per dl; arterial-ascitic fluid glucose gradient greater than 60 mg per dl.(ABSTRACT TRUNCATED AT 250 WORDS)

Pleural effusion

The sensitivity and specificity of Light's criteria for detection of exudates have been measured in many studies and are usually reported to be around 98% and 80%, respectively. This means that although Light's criteria are relatively accurate, twenty percent of patients that are identified by Light's criteria as having exudative pleural effusions actually have transudative pleural effusions. Therefore, if a patient identified by Light's criteria as having an exudative pleural effusion appears clinically to have a condition that usually produces transudative effusions, additional testing is needed. In such cases, albumin levels in blood and pleural fluid are measured. If the difference between the albumin level in the blood and the pleural fluid is greater than 1.2 g/dL (12 g/L), this suggests that the patient has a transudative pleural effusion. However, pleural fluid testing is not perfect, and the final decision about whether a fluid is a transudate or an exudate is based not on

[Diagnostic value of laboratory examination of ascites fluid (author's transl)].

Measurement of lactate dehydrogenase (LDH), glucose and protein was performed in ascites fluid of 44 patients in addition to bacteriological and cytological examinations. In patients with cirrhosis of the liver protein content of ascites was low, LDH normal, and the ascites/serum ratio of glucose concentration was higher than 1. These values were statistically significant different from the values in patients with tumorous or inflammatory disease of the peritoneum - protein and LDH in the ascites fluid being high and the ascites/serum ratio of glucose concentration being below 1. Cirrhosis however and tumors of the liver could not be differentiated by this method. Ascites from patients with cardiac failure had high protein content. In patients with liver cirrhosis high concentrations of protein in ascitic fluid may mean possibly a better survival time.