alcohol use disorders

**DEFINITION / DSM-5 CRITERIA (≥2 in 12 months)** Impaired control: larger amounts/longer than intended; unsuccessful efforts to cut down; much time spent obtaining/using/recovering; craving. Social impairment: failure to fulfill role obligations; continued use despite social/interpersonal problems; activities given up. Risky use: use in hazardous situations; continued use despite physical/psychological problems. Pharmacologic: tolerance; withdrawal. Severity: mild (2-3), moderate (4-5), severe (≥6). DSM-5 merged the older "abuse" and "dependence" categories.

**PATHOPHYSIOLOGY** - Ethanol enhances GABA-A inhibitory transmission and inhibits NMDA glutamate receptors → CNS depression. - Chronic use causes downregulation of GABA-A and upregulation of NMDA receptors → tolerance. Abrupt cessation produces unopposed excitation (withdrawal). - Reward pathway (mesolimbic dopamine, opioid system) drives reinforcement and craving. - Metabolism: alcohol dehydrogenase (ethanol → acetaldehyde, produces NADH) → acetaldehyde dehydrogenase (→ acetate). Excess NADH causes a high NADH/NAD+ ratio, leading to: lactic acidosis, hypoglycemia (impaired gluconeogenesis), fatty liver (increased fatty acid synthesis, decreased β-oxidation), and ketoacidosis. Zero-order kinetics at high levels. The MEOS (CYP2E1) is induced by chronic use (increases metabolism of other drugs, such as acetaminophen toxicity risk, and warfarin changes). - East Asian populations often carry ALDH2 variants (flushing, protective). - Genetics: ~50% heritable; risk is higher with a family history.

**CLINICAL FEATURES / COMPLICATIONS** - **Liver:** hepatic steatosis (reversible) → alcoholic hepatitis (AST:ALT >2:1, ↑GGT, ↑bilirubin, fever, tender hepatomegaly, neutrophilia; Mallory bodies on biopsy) → cirrhosis (portal hypertension, varices, ascites, hepatic encephalopathy, hepatocellular carcinoma). - **Neuro:** Wernicke encephalopathy (thiamine/B1 deficiency; triad of confusion, ataxia, ophthalmoplegia/nystagmus; mammillary body lesions); Korsakoff syndrome (anterograde and retrograde amnesia with confabulation); cerebellar vermis degeneration; peripheral neuropathy; Marchiafava-Bignami disease (corpus callosum demyelination). - **GI:** gastritis, peptic ulcer, Mallory-Weiss tears, Boerhaave syndrome, acute and chronic pancreatitis, esophageal and other cancers (head/neck, esophageal SCC, liver, breast, colorectal). - **Cardiac:** dilated cardiomyopathy, "holiday heart" (atrial fibrillation), hypertension. - **Heme:** macrocytosis (MCV ↑), folate deficiency, sideroblastic anemia, thrombocytopenia. - **Other:** hypoglycemia, alcoholic ketoacidosis (↑ anion gap; treat with dextrose/thiamine/fluids), hypomagnesemia, hypophosphatemia (especially on refeeding), fetal alcohol syndrome, increased trauma and suicide risk, gout. - Lab markers: ↑GGT, ↑MCV, AST:ALT >2:1, ↑carbohydrate-deficient transferrin (CDT).

**ALCOHOL INTOXICATION** Disinhibition, slurred speech, ataxia, nystagmus, memory impairment (blackouts), stupor/coma and respiratory depression at high levels.

**WITHDRAWAL (timeline from last drink)** - 6-24 h: tremor, anxiety, insomnia, nausea, autonomic hyperactivity (tachycardia, HTN, diaphoresis). - 12-48 h: alcoholic hallucinosis (visual, with intact sensorium). - 12-48 h (peak 24-48 h): withdrawal seizures (generalized tonic-clonic). - 48-96 h: delirium tremens (DTs): disorientation, fluctuating consciousness, hallucinations, severe autonomic instability, fever. Mortality is significant if untreated. - Assess with the CIWA-Ar scale. - Treatment: benzodiazepines (symptom-triggered or fixed; lorazepam/oxazepam preferred in liver disease because they are glucuronidated and bypass CYP metabolism, which is the "LOT" drugs mnemonic: Lorazepam, Oxazepam, Temazepam); long-acting agents (chlordiazepoxide, diazepam) for others. Give **thiamine BEFORE glucose** to avoid precipitating Wernicke encephalopathy. Also give folate, multivitamins, and replace Mg. Phenobarbital is an alternative/adjunct. Beta-blockers or clonidine alone should not be used as monotherapy (they mask signs without preventing seizures or DTs).

**MANAGEMENT OF AUD (long-term)** - Screening: CAGE (Cut down, Annoyed, Guilty, Eye-opener; ≥2 positive is clinically significant), AUDIT-C, single-question screen. Brief intervention (SBIRT). - Psychosocial: motivational interviewing, CBT, Alcoholics Anonymous, 12-step facilitation, and treatment of co-occurring psychiatric disorders. - Pharmacotherapy: - **Naltrexone** (opioid antagonist; reduces craving and heavy drinking; contraindicated with opioid use/need; caution in liver failure; also available as monthly IM injection). - **Acamprosate** (NMDA modulator/GABA effects; helps maintain abstinence; renally cleared; use in liver disease). - **Disulfiram** (inhibits acetaldehyde dehydrogenase → acetaldehyde accumulation → flushing, headache, nausea, vomiting, hypotension; needs motivated, compliant patient; hepatotoxic). Metronidazole, some cephalosporins, and procarbazine can cause disulfiram-like reactions. - Second-line: topiramate, gabapentin, baclofen (can be used in cirrhosis). - Liver transplant evaluation for end-stage disease with sustained abstinence/engagement in treatment.

**HIGH-YIELD PEARLS** - Most common cause of preventable liver disease and a leading cause of cirrhosis in the US. - Alcohol withdrawal is one of few withdrawal syndromes that can be fatal (along with benzodiazepines/barbiturates), unlike opioid withdrawal (flu-like, not life-threatening). - Pregnancy: no safe level; causes fetal alcohol spectrum disorder (microcephaly, smooth philtrum, thin upper lip, short palpebral fissures, intellectual disability; leading preventable cause of intellectual disability). - Wernicke can be precipitated by glucose-only administration in a thiamine-deficient patient. - Differentiate DTs (disorientation, autonomic instability, 48-96 h) from alcoholic hallucinosis (clear sensorium, earlier). - Drug interactions: acute use inhibits CYP450, chronic use induces it (CYP2E1). - Alcohol is a risk factor for pancreatitis (along with gallstones, the top two causes of acute pancreatitis; mnemonic "GET SMASHED": Gallstones, Ethanol, Trauma, Steroids, Mumps, Autoimmune, Scorpion sting, Hypertriglyceridemia/Hypercalcemia, ERCP, Drugs).