Detecting undisclosed methamphetamine and heroin abuse is a challenge for life underwriters and medical directors. A common clinical assumption is that if substance abusers experience liver damage, it will be indicated by elevated serum transaminases. The following case suggests that assumption may not be true for heavy substance abusers who consume no or minimal alcohol.

This report describes a 44-year-old male with long-term use of inhaled combined methamphetamine and heroin (“speedballs”) and minimal alcohol use, whose transaminases remained normal while episodes of acute liver failure and transient hepatic encephalopathy from hyperammonemia were observed. In this case, a fatal motor vehicle accident occurred following the sudden onset of hepatic encephalopathy hours after consuming a “speedball.”

Normal transaminases may not be proof of a normal healthy liver among methamphetamine and heroin abusers.

Detecting undisclosed methamphetamine and heroin abuse is a challenge for life insurance underwriters and medical directors. This case suggests that there may be a gap in the traditional clinical understanding about the relationship between substance abuse and its effect on liver function.

Liver biochemical and function tests are frequently utilized as screening tests for the presence of liver damage or dysfunction. Until recently, liver blood tests were referred to as liver function tests (LFTs). This terminology was misleading since many of the tests reflecting the health of the liver are not direct measures of its function. Additionally, liver biochemical tests may be abnormal in patients with a healthy liver. Therefore, the term liver function tests, or LFTs, has been replaced by the term liver blood tests.1 

The liver has a variety of transaminases to synthesize and break down amino acids and to interconvert energy storage molecules. The concentrations of these in the serum are normally low. However, if the liver is damaged, the hepatocyte cell membrane becomes more permeable, and some of the enzymes leak out into the blood stream. The two transaminases commonly measured are alanine transaminase/aminotransferase (ALT) and aspartate transaminase/aminotransferase (AST). These were previously called the serum glutamate-pyruvate transaminase (SGPT) and the serum glutamate-oxaloacetate transaminase (SGOT).

It is well recognized that alcohol abuse leads to liver injury that is associated with elevated transaminases. Patients who abuse only alcohol experience elevated transaminases that become higher and more sustained with increases in alcohol consumption amount and frequency. This finding probably explains why conventional clinical wisdom also associates elevated transaminases with substance abuse and consequent liver injury.

However, personal experience in life expectancy underwriting practice over many years has revealed that those patients who combine opioids with alcohol typically have much lower levels of liver transaminase results that appear sporadically instead of chronically. The classic signs and symptoms of alcohol abuse are still present, but the effect on the liver is much reduced relative to that experienced by alcohol-only abusers.

Among patients who consume large quantities of methamphetamine and no alcohol, there have been case reports of normal liver transaminase results leading to the conclusion of no liver damage.2 In these case reports, hyperammonemic encephalopathy was observed associated with methamphetamine consumption 8 to 10 hours previously, yet the authors did not associate this with any impairment of the liver, stating “As both cases had normal liver function tests, the liver toxicity cannot be the reason for hyperammonemia.”

This case report describes a 44-year-old man, who had a history of previous transient hepatic encephalopathy (HE) episodes. One hyperammonemic encephalopathy episode resulted in an emergency department (ED) visit. The patient had inhaled his usual combination of methamphetamine and heroin (“speedball’) hours before the onset of his HE. In the ED, he disclosed his heroin abuse but not his methamphetamine abuse. Liver blood tests were normal.

Thus, like the authors of the above case reports who did not link methamphetamine abuse and hyperammonemic encephalopathy to liver damage or failure, this case is consistent with the assumptions of the ED attending physicians. Normal liver blood tests were found in this patient at the time he was experiencing hyperammonemic encephalopathy, and thus no liver damage or liver failure was recognized.

A 44-year-old white male was underwritten in 2022 for a life expectancy in a legal matter. The records reviewed included a series of emergency department visit records, as well as a deposition by the wife. Of the multiple ED visits, there was only one in which this unemployed patient and ex-felon was actively experiencing altered mental status at the time of admission, testing positive for hyperammonemia (46 mcmol/L) with normal transaminases. A urine toxicology panel was positive for opioids and methamphetamine.

In other ED visits, the patient disclosed that he snorted 6 to 12 bags of heroin each day for the previous several years. He did not disclose any of his methamphetamine use even though his urine toxicology results were consistently positive for methamphetamine as well as opioids. He also reported a history of a motor vehicle accident (MVA) injuring a motorcyclist, and injury from walking into a door in a restaurant with onset of altered mental status that eventually resolved without intervention.

At the ED visit when the patient was actively experiencing HE, the patient had uncontrolled hypertension, was obese with a BMI of 34, and had bilateral lower extremity 3+ pitting edema. Investigations disclosed very elevated mixed hyperlipidemia and a borderline ECG. An echocardiogram showed mild concentric modeling of the left ventricle. The patient admitted that he had been noncompliant with his antihypertensive and lipid-lowering medication for 6 months or more.

The primary effort at that time was focused on ruling out stroke or heart failure as the underlying cause of the altered mental status. CT of the head showed a possible hemorrhage in the basal ganglia, but subsequent investigations over the next few days determined that this finding was actually a cavernoma.

The ED attending physicians noted that the liver blood tests were normal. It was assumed that the liver was normal and that any liver failure due to damage from substance abuse was not present despite the presence of hyperammonemia and symptoms consistent with hepatic encephalopathy and acute liver failure.

In all his ED visits, the patient denied drinking very much alcohol, and the telltale signs and symptoms of alcohol abuse (gastrointestinal disorders like gastritis, reflux, melena; fatty liver; skin rashes; elevated HDL and/or MCV) were absent. Yet acute liver failure was clearly present as indicated by the elevated ammonia in the presence of altered mental status.

What the patient did admit to and/or was diagnosed with over the course of his multiple ED visits include: history of intravenous drug use, history of withdrawal (sweating, anxiety, diarrhea), altered mental status, acute neurologic deterioration, blackouts, lethargy, confusion, slurred speech, head injury from walking into door, nose injury, vomiting, convulsions, tachycardia, palpitations, depression, chronic daily headaches/migraines, decreased concentration, drowsiness, photophobia, intermittent visual changes, constipation (typically only one bowel movement a week), antalgic gait, paresthesias, poor sleep, chronic wrist pain from wrist fracture, back pain, shoulder pain, low hematocrit, low hemoglobin, fractured clavicle, fractured orbital floor, and claims of being “stressed.”

The event of issue in this legal case was related to this patient going into one of his many HE spells while he was driving, with his wife in the front passenger seat and his 2-year-old granddaughter sitting in the back seat.

It was a clear, dry day on a straight freeway when the patient lost consciousness while driving several hours after his last drug use and lost control of the car. As the car spun around, another car hit the patient's driver side door and t-boned the car at full speed with maximum impact. The patient ended up with internal injuries and died a week later.

Had the timing and speed of this MVA been any different, resulting in an impact to the rear of the car, it would have been the granddaughter in the back seat who would have died from this MVA instead of the driver. The patient would have then walked away from this MVA and lived another day to cause yet another MVA with possible death and/or injury to one or more people. This MVA was another instance where the patient experienced HE and blacked out behind the wheel, this time ending up in his own injury and death.

This is a case that involves hyperammonemia, normal liver blood tests, minimal alcohol use, and very high daily ingestion of methamphetamine and heroin. The current clinical and underwriting impression is that when alcohol damages the liver sufficiently, transaminases will be elevated. However, methamphetamine and heroin abuse appear to deplete and/or exhaust the liver's detoxification process that in turn induces acute liver failure and its resulting transient hyperammonemia. The hypothesis that hyperammonemia arises from methamphetamine's direct effect on the brain is not credible, as the assumption that normal liver blood tests associated with methamphetamine abuse means no liver damage, and thus no liver failure is not supported by the direct case evidence.

In essence, a huge bolus of combined methamphetamine and heroin (“speedball”) taken many times each day that is detoxified each time by the liver would reasonably deplete and/or exhaust the liver for a period of time during which it could not detoxify blood ammonia. The eventual recovery of the liver's detoxifying function after each bolus is processed is shown by the spontaneous recovery from the associated altered mental status/hepatic encephalopathy (HE).

As the HE arises many hours after the methamphetamine and heroin are consumed, this has not been clinically associated with any of the direct effects of intoxication. It is likely that the liver's transient inability to detoxify blood ammonia is linked to the possible depletion and/or exhaustion of glutathione and/or any of the critical antioxidants used in the liver's detoxifying pathway.3 

The series of ED visits demonstrated increasing severity over time of the patient's HE signs and symptoms that follows the pattern of increasing severity described by the West Haven criteria for grading HE.4 The patient displayed a pattern of subclinical Grade 0 to Grade 1 HE signs and symptoms for a period of time until more serious overt Grade 2 and Grade 3 levels associated with accidents and injuries occurred. Both subclinical and overt HE predict a poor prognosis.5 

Every life underwriter and medical director needs to know the difference in signs and symptoms between the different types of substances abused by potential applicants for life insurance. These individuals may or may not disclose the nature and extent of their substance abuse. As this case illustrates, the risk associated with acute onset of hepatic encephalopathy is extreme, as motor vehicle accidents can arise that cause death and/or injury not only to the substance abuser but to everyone around that individual as well.

Normal liver blood tests among methamphetamine and/or heroin abusers who consume minimal alcohol do not necessarily imply that their livers are healthy and not subject to transient acute liver failure and HE from depletion and/or exhaustion.

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Methamphetamine-associated hyperammonemic encephalopathy – case report
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Astrocyte swelling in hepat-ic encephalopathy: molecular perspective of cytotoxic edema
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