Alcohol and Drug Abuse: Pathology

Introduction

I. Alcohol Abuse

Ethanol metabolism

1. Alcohol dehydrogenase pathway
   • Ethanol → acetaldehyde
   • Acetaldehyde → acetate, by aldehyde dehydrogenase.
2. Microsomal ethanol-oxidizing system
   • Predominantly CYP2E1 in smooth endoplasmic reticulum.
   • Important in chronic heavy drinking.
   • Produces reactive oxygen species and induces drug metabolism.
3. Catalase pathway
   • Minor role.

Important metabolic consequences

• Alcohol dehydrogenase generates excess NADH, increasing the NADH/NAD⁺ ratio.
• This inhibits fatty-acid oxidation and promotes lipid synthesis, producing hepatic steatosis.
• Increased NADH also favors conversion of pyruvate to lactate, causing lactic acidosis.
• Acetaldehyde forms protein adducts, causes lipid peroxidation, mitochondrial dysfunction, cytoskeletal injury, and membrane damage.
• CYP2E1 generates reactive oxygen species, causing oxidative injury.
• Chronic alcohol use induces CYP2E1, increasing toxicity from drugs such as acetaminophen.

Pathologic effects of chronic alcohol use

1. Liver

A. Hepatic steatosis

• Earliest and most common lesion.
• Liver is enlarged, soft, yellow, and greasy.
• Histology: macrovesicular fat accumulation, initially centrilobular.
• Usually reversible with abstinence.

B. Alcoholic steatohepatitis

• Hepatocyte ballooning degeneration and necrosis
• Neutrophilic infiltration
• Steatosis
• Perivenular and perisinusoidal fibrosis, especially in zone 3
• Mallory-Denk bodies: eosinophilic cytoplasmic inclusions composed largely of damaged keratin intermediate filaments
• Cholestasis may occur

C. Cirrhosis

• Progressive bridging fibrosis and regenerative nodules.
• Early cirrhosis may be micronodular; later it becomes mixed macro- and micronodular.
• Complications:
  • Portal hypertension
  • Ascites
  • Splenomegaly
  • Variceal bleeding
  • Hepatic encephalopathy
  • Hepatocellular carcinoma

2. Gastrointestinal tract and pancreas

• Acute gastritis, mucosal erosions, and gastrointestinal bleeding
• Esophagitis and increased risk of reflux
• Malabsorption due to mucosal injury and poor nutrition
• Acute pancreatitis
• Chronic pancreatitis with fibrosis, acinar loss, ductal obstruction, and calcification
• Increased risk of pancreatic carcinoma

3. Nervous system

• Acute intoxication: impaired judgment, incoordination, slurred speech, coma, and respiratory depression at very high blood levels.
• Peripheral neuropathy: often related to direct toxicity and thiamine deficiency.
• Cerebellar degeneration: gait ataxia due to loss of Purkinje cells, predominantly in the anterior superior vermis.
• Wernicke encephalopathy due to thiamine deficiency:
  • Confusion
  • Ataxia
  • Ophthalmoplegia/nystagmus
  • Lesions around third ventricle, aqueduct, and mammillary bodies
• Korsakoff syndrome:
  • Memory loss
  • Confabulation
• Central pontine myelinolysis may occur with rapid correction of hyponatremia in alcohol-dependent or malnourished individuals.

4. Cardiovascular system

• Dilated cardiomyopathy with cardiac enlargement and systolic dysfunction
• Arrhythmias, especially after binge drinking, termed “holiday heart”
• Hypertension
• Increased risk of stroke and sudden cardiac death

5. Hematologic and nutritional effects

• Macrocytic anemia due to folate deficiency and direct marrow toxicity
• Thrombocytopenia
• Leukopenia in severe disease
• Poor wound healing and susceptibility to infection
• Deficiency of thiamine, folate, pyridoxine, vitamin A, and other nutrients

6. Reproductive and fetal effects

• Testicular atrophy and reduced testosterone in men
• Menstrual abnormalities and infertility in women
• Alcohol use in pregnancy may cause fetal alcohol spectrum disorder:
  • Growth retardation
  • Microcephaly
  • Intellectual disability
  • Facial abnormalities: short palpebral fissures, smooth philtrum, thin upper lip
  • Congenital heart defects may occur

7. Cancer

• Oral cavity
• Pharynx
• Larynx
• Esophagus
• Liver
• Breast
• Colorectum

II. Drug Abuse

General mechanisms of injury

1. Direct toxic effects
2. Overdose and respiratory depression
3. Vasoconstriction and ischemia
4. Hyperthermia and rhabdomyolysis
5. Infections related to intravenous administration
6. Contaminants or adulterants
7. Trauma, violence, and accidents
8. Withdrawal and dependence

• HIV infection
• Hepatitis B and C
• Infective endocarditis, commonly right-sided
• Septic emboli
• Skin abscesses
• Talc and foreign-body granulomatosis

Major drugs and their pathology

Cocaine: important pathology

Effects

• Coronary vasospasm and thrombosis → myocardial ischemia/infarction, even in young persons
• Tachyarrhythmias and sudden death
• Severe hypertension → intracerebral hemorrhage or ischemic stroke
• Hyperthermia → rhabdomyolysis, acute renal failure, disseminated intravascular coagulation
• In pregnancy: placental abruption, fetal growth restriction, and fetal death
• Chronic nasal insufflation: ischemic necrosis and perforation of nasal septum

Opioids: important pathology

Acute overdose

• Coma
• Pinpoint pupils
• Respiratory depression
• Pulmonary edema
• Death due to hypoxia

Chronic intravenous use

• Infective endocarditis
• Viral hepatitis and HIV
• Foreign-body granulomas in lung due to injected talc or cellulose
• Renal disease, including focal segmental glomerulosclerosis in some heroin users
• Skin ulcers and abscesses

Tobacco as a drug of abuse

Major effects

• Lung carcinoma and cancers of oral cavity, larynx, esophagus, pancreas, bladder, kidney, and others
• Chronic bronchitis, emphysema, and COPD
• Atherosclerosis, ischemic heart disease, peripheral vascular disease, and stroke
• Adverse pregnancy outcomes: spontaneous abortion, prematurity, low birth weight, and fetal growth restriction

Conclusion