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, and 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 and 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, the alcohol dehydrogenase isoform present in the stomach metabolizes a minor quantity of alcohol. 
The quantity of alcohol metabolized in the stomach depends on the fed state and gastric emptying time. During fasting, the alcohol rapidly reaches the small intestine and is 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+ is reduced to generate NADH. The genetic polymorphism of ADH and ALDH genes has been associated with 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. Individuals with increased ADH activity or decreased ALDH activity may have an increased accumulation of aldehyde and a higher risk of liver diseases.

The second enzyme CYP2E1 metabolizes ethanol when the 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 is an enzyme that 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 results in metabolic adaptations of cells and chronic exposure leads 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 pathways. The availability of NADH and acetyl CoA inhibits the energy-liberating pathways such as glycolysis, tricarboxylic acid cycle, fatty acid oxidation, and pyruvate oxidation.
On the other hand, cells attempt to normalize the NAD+/NADH ratio by favoring the conversion of pyruvate to lactate and the ketogenic pathway. The conversion of pyruvate to lactate partially rescues the NAD+/NADH but chronic exposure decreases the availability of 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 acids by inhibiting beta-oxidation of fatty acids. 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, and cirrhosis:
The hepatocellular damage can affect the liver function by decreasing liver function such as the 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:
a) 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 is exclusively synthesized and secreted by the liver. In addition, albumin has a half-life of approximately 21 days which allows monitoring of chronic defects in the liver. The caveat is that albumin may be lowered in other conditions such as malnutrition, and 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. Acute hepatocellular disease differs from a chronic form with normal albumin and prothrombin time.

Assessing detoxification function:
Bilirubin is conjugated by the enzyme UDP-glucuronosyl transferase and excreted via the bile. The majority of ammonia is handled by the liver and converted into urea in the liver. Therefore, the evaluation of bilirubin, urea, and ammonia is used to assess the detoxification function of the liver. Elevated urea and ammonia are suggestive of defective excretion of these metabolites whereas increased ammonia and bilirubin with normal or blood urea are suggestive of 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 specific markers for liver injury and are elevated during muscle injury, interpretation of the 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 chronic alcoholic liver disease. In addition, mild elevated GGT also suggests 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 (Cut, annoyed, guilty, and eye)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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