Alcoholic Liver Disease: Clinical Presentation and Biochemical Correlation

PBL Case Objective
a) Describe how alcohol is metabolized in the body.
b) Discuss the cause of hematological abnormalities if any.
c) Discuss how biochemical results correlate with the provisional diagnosis.
d) Discuss any test recommendations.
e) Discuss the provisional diagnosis.

Clinical Presentation
A 40 years old man was admitted to the hospital with hematemesis, loss of consciousness, swelling of lower limbs. The patient had a history of alcoholism with daily consumption of approximately 1 to 2 L of beer every day for the past ten years. the physical examination showed hepatomegaly, mild ascites. The hematological and biochemical results are presented below.

Alcohol Metabolism occurs in the liver
The liver is the major tissue for alcohol metabolism in the body. Before alcohol reaches the liver, alcohol dehydrogenase isoform present in the stomach metabolizes minor quantity of alcohol. The quantity of alcohol metabolized in the stomach depends on the fed state, gastric emptying time. During fasting, the alcohol rapidly reaches the small intestine and absorbed into the bloodstream which increases the bioavailability.

In the liver, two enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) catalyzes the conversion of ethanol to acetyl CoA and NAD+ are reduced to generate NADH. The genetic polymorphism of ADH and ALDH genes have associated the activity of the ADH and ALDH enzymes and subsequently sensitivity to alcohol. The studies have shown ethnic variations in alcoholism and alcoholism associated disorders. The individuals with increased ADH activity or decreased ALDH activity may have increased accumulation of aldehyde and a higher risk of liver diseases.

The second enzyme CYP2E1 metabolizes ethanol when blood concentration of alcohol is higher. The CYP2E1 (microsomal ethanol oxidizing enzyme )is a cytochrome P450 family enzyme that has a low affinity (Ka= 10nM) for ethanol. This inducible enzyme is more active in an individual with low ADH activity or chronic alcohol consumption. The other minor pathways for alcohol metabolism have been reported but the physiological significance is unknown.

Figure 1: Metabolism of Ethanol. Alcohol is metabolized in the liver to form acetate. The formation of acetaldehyde is catalyzed by two separate enzymes depending on the ethanol concentration in the body. Alcohol dehydrogenase an enzyme catalyzes the formation of acetaldehyde with the generation of NADH. The second enzyme CYP2E1 catalyzes the same reaction but requires NADPH for its activity.

Metabolic changes and Liver Pathology:

The oxidation of alcohol in the liver generates the acetyl CoA& NADH and decreases the ratio of CoA/ acetyl CoA & NAD+/NADH. The altered equilibrium of these metabolites result in metabolic adaptations of cells and chronic exposure lead to liver diseases. The metabolic adaptations in the liver include:
i) Alcohol metabolism alters the hepatic redox state
Alcohol dehydrogenase and Aldehyde dehydrogenase generates each generates one molecule of NADH in the process of converting ethanol to acetate. The decreased NAD+/NADH ratio resulting from increased cellular NADH disrupts redox equilibrium and dysregulation of various glucose and lipid metabolic pathway. The availability of NADH and acetyl CoA inhibits the energy-liberating pathways such as glycolysis, tricarboxylic acid cycle, fatty acid oxidation, pyruvate oxidation.
On the other hand, cells attempt to normalize the NAD+/NADH ratio by favoring the conversion of pyruvate to lactate and ketogenic pathway. The conversion of pyruvate to lactate partially rescues the NAD+/NADH but the chronic exposure decreases the availability pyruvate for a gluconeogenic pathway, hypoglycemia, and lactic acidosis.
ii) Alcohol metabolism increases triacylglycerol synthesis, lipid storage, and ketogenesis
In the liver, alcohol increases fatty acid by inhibiting beta-oxidation of fatty acid. The increased concentration of glyceraldehyde-3-phosphate and free fatty acid enhance the formation of triacylglycerol and secretion of VLDL. In severe alcoholism, the excess acetyl CoA generated is utilized for ketogenesis and released into the bloodstream resulting in ketoacidosis.

iii) Excessive chronic alcohol consumption can cause fatty liver, hepatocellular damage, cirrhosis
The hepatocellular damage can affect the liver function by decreasing liver function such as synthesis of proteins and clotting factors, detoxification of bilirubin and ammonia etc. The hepatomegaly, gross histological arrangement of hepatocytes and altered serum bilirubin and enzymes are the characteristic feature of liver cirrhosis.

Figure 2: Metabolic derangement in alcoholic liver disease

Disease correlation with Clinical Chemistry Parameters
The clinical chemistry parameters can be categorized into three different categories:
i) Assessing synthetic function
The synthetic function of the liver may be assessed by measuring the albumin and clotting factor. The albumin constitutes 60% of the plasma and exclusively synthesized and secreted by the liver. In addition, albumin has a half-life of approximately 21 days that allows monitoring of chronic defect in the liver. The caveat is that albumin may be lowered in other conditions such as malnutrition, proteinuria. Therefore, the measurement of albumin with prothrombin time can provide a better understanding of defective tissue. In this particular clinical case, the albumin is lower with prolonged prothrombin time suggesting a chronic hepatocellular disease. The acute hepatocellular disease differs from a chronic form with normal albumin and prothrombin time.

ii) Assessing detoxification function
Bilirubin is conjugated by enzyme UDP-glucuronosyl transferase and excreted via bile. The majority of ammonia are handled by the liver and converted into urea in the liver. Therefore, the evaluation of bilirubin, urea, and ammonia are used to assess the detoxification function of the liver. Elevated urea and ammonia are suggestive of defective excretion these metabolites whereas increased ammonia and bilirubin with normal or blood urea are suggestive of the hepatocellular disease.

c) Assessing hepatocellular damage
The extent of hepatocellular damage can be assessed using liver enzymes ALT and AST. Although both ALT and AST are not a specific marker for liver injury and elevated during muscle injury, interpretation of AST/ALT ratio (de Ritis ratio) along with ALP and GGT provides liver injury. During acute viral hepatitis, ALT is rapidly elevated and the activity in serum is higher than AST. In contrast, the AST is mildly elevated with higher serum activity compared to ALT (AST/ALT ratio >2) is suggestive of the chronic alcoholic liver disease. In addition, mild elevated of GGT also suggest the chronic alcoholic liver disease.

d) Decreased hemoglobin concentration:
The hemoglobin is synthesized in bone marrow in response to erythropoietin. During chronic liver disease, the erythropoietin synthesis is also decreased leading to decreased hemoglobin.

Additional Investigation recommended for treatment prognosis
CAGE questionnaire for alcohol dependency
Assessment of proteinuria and serum creatinine (renal function)
Histopathological examination of liver
Carbohydrate-deficient transferrin

Provisional Diagnosis
The case presentation and laboratory results suggestive of chronic alcoholism with hepatocellular damage.

AASLD practice guidelines Alcoholic liver disease
Cederbaum AI 2002, Clinical liver disease
McPherson et al, 2006 BMJ

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