Chenodiol

Limits on what this shows

• Null findings: Concentrations of 20 to 150 uM were not compared with human hepatocellular exposure in any source read. UDCA alone caused only 30% depolarization and UDCA potentiated CDCA toxicity [8][9]; tauroursodeoxycholate was hepatoprotective in the isolated mitochondria model [11]. No clinical mitochondrial marker (lactate, mitochondrial DNA, respirometry) was found for chenodiol users.
• At-risk subgroups: Pre-existing liver disease or cholestasis, which the label contraindicates [1][3]. Combined UDCA exposure is potentiating in vitro [8][9] but is a hypothesis for clinical use.

Direction

Excess or toxicity of the drug's own molecule. Not a nutrient depletion (Hard Rule 2).

Regulatory status

The labels do not mention mitochondria [1][2][3]. They carry a hepatotoxicity warning and aminotransferase monitoring; the label does not attribute the hepatotoxicity to mitochondrial injury.

Population evidence

None in humans. Rolo 2001 [7]: freshly isolated rat liver mitochondria; CDCA at 20 uM (swelling, calcium flux) and 50 uM (membrane potential) induced permeability transition with depolarization, matrix calcium release and osmotic swelling, prevented by cyclosporin A and ruthenium red (read as a repository PDF summary). Rolo 2003 [8]: isolated rat hepatocytes, 150 uM CDCA for 1 to 4 hours produced a marked, almost complete fall in mitochondrial potential; cyclosporin A reduced depolarization and cell killing. Rolo 2004 [9]: human HepG2 cells, CDCA lowered mitochondrial membrane potential and triggered caspase-9 apoptosis. Conjugates, the forms the liver secretes in bile per the label [1]: glycochenodeoxycholate induced permeability transition in rat mitochondria in a dose- and calcium-dependent manner, reduced by antioxidants [10]; glyco- and taurochenodeoxycholate caused stepwise mitochondrial destruction in isolated mitochondria with the adenine nucleotide translocase as a proposed target [11]. All Tier B (mechanistic, this molecule or its conjugates).

Mechanism

Present and named: permeability transition pore opening with oxidant and calcium dependence [7][10][11].

Counter-evidence held on record

Counter-evidence and confounding Isolated mitochondria and hepatocyte cultures do not reproduce first-pass handling, albumin binding (about 98% in plasma [2]) or bile acid transporters. The clinical correlate, reversible aminotransferase elevation, is documented in the labels but its mechanism is not established there. Framing caution This is a drug-toxicity mechanism, not a nutrient shortfall. Do not recommend CoQ10, NAD precursors or any mitochondrial supplement from this entry. Liver monitoring per the label is the relevant action.

Limits on what this shows

• Null findings: No trial measured malondialdehyde, glutathione, F2-isoprostanes or antioxidant capacity in people taking chenodiol. The ROS data come from conjugate exposures well above what the labels describe in plasma.
• At-risk subgroups: Not defined. CTX patients carry a disease-driven oxidative burden before treatment [14].

Direction

Mixed: excess oxidant load in vitro (toxicity) and one reverse-direction (protective) clinical case. Neither is a nutrient deficiency.

Regulatory status

Not mentioned in the labels [1][2][3].

Population evidence

Chu 2003 [12]: rat hepatocytes exposed to glycochenodeoxycholic acid 0 to 400 uM for 0.5 to 3 hours; dose-dependent ROS generation; Cu/Zn-SOD stable; catalase fell only at 400 uM; peroxiredoxin I and II fell at 200 to 400 uM; necrosis predominated at 200 uM and above. Sokol 2001 [10]: the same conjugate induced permeability transition in rat mitochondria, with antioxidants reducing both the transition and hydroperoxide generation. Reverse direction: Kinoshita 2004 [13], a single CTX patient, reported that CDCA treatment improved LDL resistance to oxidation, raised CETP activity and lowered HDL cholesterol (abstract read through a summarizer). Disease context: an autopsy-diagnosed CTX case showed carboxymethyl-lysine staining, an oxidative damage marker, in histiocytes [14]; that is the disease, not the drug. All Tier B or case-level.

Mechanism

Named for the excess direction (mitochondrial ROS, with NF-kappaB activation preceding death) [10][12]. For the reverse direction the case report attributes the change to correction of CDCA deficiency [13].

Counter-evidence held on record

Counter-evidence and confounding The two directions come from different systems (rat cells versus one human patient) and cannot be netted. Confounding by indication applies to the case report: CTX LDL oxidation may change with cholestanol lowering independent of CDCA itself. Framing caution Not a basis for antioxidant supplementation. The single case report is not an effect estimate.

Limits on what this shows

• Null findings: No chenodiol trial, CTX cohort or label reports iron, ferritin or transferrin saturation. The two retrieval summaries of [15] disagreed on the author list, so the DOAJ record was used for authorship.
• At-risk subgroups: Not defined. Menstruating women and CKD patients carry independent iron risk.

Direction

Retention or functional restriction (higher hepcidin, lower circulating iron). Not a dietary iron deficiency, and supplementation would not address the proposed mechanism.

Regulatory status

Not mentioned in the labels [1][2][3].

Population evidence

Wang et al., Nutrients 2022 [15]: HepG2 cells treated with glycochenodeoxycholate increased hepcidin expression nearly 2-fold through FXR with BMP6 and ALK3 signaling; mice given high-dose glycochenodeoxycholate showed about 30% lower serum iron and lower hemoglobin and hematocrit. Observational CKD patients with elevated glycochenodeoxycholate had hepcidin 43.85 +/- 25.48 ng/mL versus 5.29 +/- 3.37 ng/mL in healthy people; no chenodiol was given to humans. Tier B (conjugate of this drug; animal and cell). Indication context: in a surgical-department study of 200 gallstone patients and 50 controls, low ferritin was more frequent in cases (64.5% versus 16.66% in men; 35.5% versus 15.38% in women) [17]. This is a pre-treatment association and points to confounding by indication.

Mechanism

Present and named (FXR to BMP6/ALK3 to hepcidin) for the conjugate. Whether therapeutic chenodiol dosing in people reaches the exposure used in mice is not established.

Counter-evidence held on record

Counter-evidence and confounding Doses in mice are not scaled to human exposure in the summary read. Gallstone patients may already have low ferritin before any drug [17]. The study's population data are CKD, where inflammation independently raises hepcidin. Framing caution This is a retention or functional-restriction signal. Iron supplementation is not recommended by this entry, and excess iron has its own risks.

Limits on what this shows

• Why no grade: Both conditions of Step 7 are met. No Tier B or C source supports even a yellow: the only bile acid and copper paper opened, Guo et al., Cell Death Discovery 2026 [27], tested taurocholic acid only (cholestatic liver injury with copper accumulation in rats and cells, plus pediatric serum copper data); chenodiol and its conjugates were not studied, and taurocholic acid is an endogenous bile acid, not a member of the drug's class. The other copper hit, Aisen 1964 [28], concerns biliary excretion of ceruloplasmin copper in rabbits with no bile acid therapy. No circulating claim: the consumer pages checked [29] make no copper or other nutrient claim, and the Antidote Research chenodiol depletion URL returned 404 [30].

Channels tried

Label text of five documents [1][2][3][4][5]: no copper mention. Web search "chenodeoxycholic acid serum copper OR ceruloplasmin OR biliary copper excretion" (results irrelevant to the drug; Aisen 1964 opened). Web search "bile acids hepatic copper accumulation cholestasis ursodeoxycholic chenodeoxycholic copper retention liver" (Guo 2026 opened; taurocholic acid only). The iron and hepcidin paper [15] was opened and did not measure copper. PubMed listing search "chenodeoxycholic acid copper" returned HTTP 429 and was not retried. Crossref, OpenAlex and Europe PMC were not attempted because direct access is blocked by organization policy.

Genuine gap or tooling-limited

Partly both. The two searches that ran found nothing drug-specific, which suggests a true literature gap, but the PubMed listing channel was blocked, so a re-check is warranted. This is a disclosed gap, not a finding of safety. Bile is the main copper excretion route, and the label contraindicates chenodiol in cholestasis, but neither point is a chenodiol finding.

Limits on what this shows

• Null findings: Pre-treatment alpha diversity did not differ between responders and non-responders [19]. No human chenodiol-only or CTX microbiome study was located.
• At-risk subgroups: Not defined. Patients with chenodiol-related diarrhea (30 to 40%) are an obvious confounding group for stool-based measures [1][2].

Direction

Compositional change (reduced alpha diversity). Neither depletion nor excess of a nutrient.

Regulatory status

The Chenodal label states that an amount of chenodiol near the daily dose reaches the colon and is converted by bacterial action to lithocholic acid [1][3]. It makes no statement about microbiome composition.

Population evidence

Lee et al., Biomedicines 2023 [18]: prospective single-center preliminary study, 15 enrolled and 13 evaluable gallbladder-stone patients, 40 healthy controls; capsules holding 114 mg UDCA and 114 mg CDCA, 2 capsules daily for 6 months; alpha diversity fell after treatment (Chao1 p < 0.01, Shannon p < 0.008, Simpson p < 0.018); Roseburia was lower before treatment than in controls and recovered after (p = 0.022). Lee and Park, Scientific Reports 2024 [19]: same enrolment (15 enrolled, 13 completed) and capsules; 8 responders (4 complete and 4 partial dissolution) versus 5 non-responders; Erysipelotrichi fell in non-responders (p = 0.039) and higher Firmicutes marked poor response. The two reports appear to describe one cohort (not confirmed). Animal: rats after bile duct ligation given CDCA by gavage for 7 days had fewer Clostridiaceae, Coriobacteriaceae and Erysipelotrichaceae [20] (English abstract page only).

Mechanism

Present: bile acid antimicrobial and signaling effects, and bacterial 7-dehydroxylation of chenodiol to lithocholic acid [1]. Not isolated for chenodiol in any human study.

Cohort test

Chenodiol was in the cohort, but only inside a fixed UDCA/CDCA combination, so effects cannot be attributed to chenodiol; the study design carries no UDCA-only or untreated comparator [18]. Graded yellow, not orange, for that reason, and because microbiome change is not a deficit. No PPI or other class finding was borrowed.

Counter-evidence held on record

Counter-evidence and confounding Tiny sample, no control arm on treatment, gallstone disease itself alters the microbiome (the cohort differed from controls before treatment), PICRUSt2 function inference was acknowledged as limited, and bile acid dosing, diet and diarrhea changed together [18][19]. Framing caution A monitoring-level observation only. Do not recommend probiotics or fiber from this entry.

Limits on what this shows

• Null findings: No tissue or blood ATP, phosphocreatine or lactate measurement in treated humans or animals was found. Fructose rescue shows the in vitro ATP loss is reversible by glycolytic supply.
• At-risk subgroups: Not defined from in vitro data.

Direction

Excess or toxicity of the drug's own molecule. Not a nutrient depletion and not a statement about energy status in treated patients.

Regulatory status

Not mentioned in the labels [1][2][3].

Population evidence

Rolo 2003 [8]: isolated rat hepatocytes, control ATP 75 +/- 3 nmol per million cells; after 4 hours of 150 uM CDCA alone ATP fell to about 50% of control, and UDCA added to CDCA lowered it further. Fructose kept ATP near control in all conditions. Rolo 2004 [9]: in HepG2 cells, ATP depletion occurred with CDCA plus UDCA; the CDCA-alone ATP value was not captured in the summary read. A statement about reduced state 3 respiration in isolated mitochondria appears in the Rolo 2001 summary [7] as a literature reference, not as a measurement in that paper. Tier B.

Mechanism

Present: permeability transition with loss of membrane potential, supported by cyclosporin A protection [8]. Shared with the Mitochondrial burden entry.

Counter-evidence held on record

Counter-evidence and confounding Fatigue or low energy in treated patients has other competing explanations (underlying disease, diarrhea, liver injury) and was not measured against ATP. The label lists muscular weakness at 14% in the CTX trial [2], a clinical outcome, not an ATP finding. Framing caution Do not link a patient's tiredness to ATP depletion from this entry. No supplement is indicated.

Limits on what this shows

• Null findings: The Ctexli trial adverse event list (diarrhea, headache, abdominal pain, constipation, hypertension, muscular weakness, URTI) includes no anemia [2]. No chenodiol study measured hemoglobin, hematocrit or arterial oxygenation.
• At-risk subgroups: Not defined.

Direction

Hematologic harm and possible iron-restriction effect. Not an oxygen-delivery nutrient deficiency; no oxygen-delivery measurement exists for chenodiol.

Regulatory status

Chenodal label: decreases in white cell count, never below 3000, in a few patients [1][3]. No anemia or hemoglobin statement in the sections read of either label [1][2][3][5].

Population evidence

Wang 2022 [15]: mice on high-dose glycochenodeoxycholate had significantly lower hemoglobin and hematocrit. Cuka et al. 2002 [16]: conference poster, human erythrocytes exposed to cholic acid, CDCA, deoxycholic acid and lithocholic acid at 50, 250, 500 and 1000 uM; lithocholic acid and CDCA were the most hemolytic, dose-related. Tier B, preclinical; the poster is not a peer-reviewed full paper.

Mechanism

For the mouse finding, the hepcidin and iron route (shared with the Iron entry). For hemolysis, membrane damage by hydrophobic bile acids at concentrations that no source read compared with plasma levels.

Counter-evidence held on record

Counter-evidence and confounding Leukopenia is a white-cell finding and does not bear on oxygen carrying. The mouse hemoglobin fall depends on the same single study as the iron entry, so it is not independent confirmation. Framing caution Not evidence of anemia or reduced oxygen carrying in chenodiol users. A complete blood count is worthwhile for symptoms, not as a drug-attribution test.