TABLE 3.
Studies using the RDRs in physiological or pathological conditions in humans or animal models1
| First author, year (reference) | Country or animal species | Group | Age | Condition(s) examined | Study design (n at end of study) | n | Main findings |
|---|---|---|---|---|---|---|---|
| Mobarhan, 1981 (99) | USA | Adults | 46–69 y | CLD (cirrhosis), zinc deficiency | RDR pre-/post- VA intervention,2 RDR compared with serum zinc | 8 | RDR changed in response to the intervention in patients with alcoholic cirrhosis and was different according to dark adaptation status. Zinc deficiency was not a limiting factor in the RDR |
| Russell, 1983 (101) | USA | Adults | 45–65 y | CLD (chronic alcoholism, cirrhosis), zinc deficiency | RDR compared with liver biopsy TLR,3 serum zinc | 26 | RDR did not predict TLR. Zinc deficiency was not a limiting factor in the RDR |
| Flores, 1984; Campos, 1987 (25, 136) | Brazil | Children | 18–85 mo | Age, infection (chicken pox), age, malnutrition | RDR pre-/post-VA intervention2 and case/control for infection in children, with 20% of them <75% of Iowan weight-for-age standard | 72 | RDR responded to intervention and then increased drastically in response to infectionWeight-for-age was not correlated with RDR response to intervention |
| Amedee-Manesme, 1987 (22) | France | Children | 2 mo–13 y | CLD (e.g., biliary atresia, portal obstruction, Alagille syndrome), age | i.m.-RDR compared with biopsy TLR3 | 11 | i.m.-RDR predicted VA status |
| i.m.-RDR pre-/post-VA intervention2 | 7 | i.m.-RDR responded to the intervention in CLD patients | |||||
| Amatayakul, 1989 (137) | Thailand | Women | 18–25 y | Oral contraceptive use | RDR pre-/post- VA intervention2 and oral contraceptive compared with intrauterine contraceptive device control | 39 | RDR responded to treatment in the only individual with elevated RDR, not possible to assess contraceptive use effect on RDR |
| Bulux, 1992 (72) | Guatemala | Elderly adults | 60–91 y | Age | RDR 7 d test/retest and time course in elderly adults | 14 | Two high RDR value individuals had a negative RDR 7 d later, and RDR peaked later than expected (6–7 h) |
| Vaisman, 1992 (100) | Israel | Adolescents | 16.3 ± 1.6 | Anorexia | RDR pre-/post-dietary modification for anorexia | 3 | RDR responded to intervention |
| RDR time course | 7 anorexic, 7 healthy | RDR time course was not different between groups | |||||
| Stoltzfus, 1993 (4) | Indonesia | Women | <50 y | Lactation | RDR pre-/post-VA intervention2 in lactating women | 139 | RDR positive prevalence started very low and did not respond to intervention |
| Infants | 7–21 d | Age, breastfeeding | RDR post-maternal VA intervention2 in infants | 131 | RDR was different according to maternal intervention group | ||
| Humphrey, 1994 (28) | Indonesia | Children | 12–59 mo | Age | RDR pre-/post-VA intervention2 in children | 345 | RDR responded to intervention |
| Tanumihardjo, 1994 (106) | Indonesia | Women | 17–41 y | Lactation, body weight | MRDR 1–2 mo test/retest in lactating women | 14 | Positive MRDRs remained positive, 1 negative MRDR remained negative, the other was 0.048 and then 0.060 on retest. Variability increased as the interval increased |
| MRDR time course | 30–33 lactating/time point, 6–8 nonlactating/time point | MRDR was higher in lactating women than nonlactating women at all time points 3–6 h | |||||
| Tanumihardjo, 1994 (29) | Indonesia | Children | 0.7–65 y | Age, malnutrition | MRDR followed by 1.57 μmol RDR 10–17 d later in children with 96% of subjects below 10th percentile of weight-for-age4 | 75 | MRDR (48% positive) did not agree with RDR (10% positive) |
| MRDR followed by 3.5 μmol RDR 3–4 wk later in children, then intervention2 and follow-up MRDR, 59% of subjects below 10th percentile of weight-for-age4 | 47 baseline, 8 follow-up | Preintervention MRDR (12% positive) agreed with RDR (11% positive) and responded to intervention | |||||
| Azaïs-Braesco, 1995 (73) | France | Elderly adults | 83 ± 6.1 y | Age | RDR 3-wk test/retest | 14 | RDR gave the same result in 11/14 individuals |
| Pre-/post-VA intervention | 5 | RDR responded to intervention | |||||
| Wahed, 1995 (41) | Bangladesh | Children | 3–36 mo | Age, malnutrition | MRDR followed by RDR correlation 3 d later in children with low weight-for-age (74% below the 75th percentile weight-for-age)5 | 49 | MRDR (20% positive) did not agree with RDR (60% positive) |
| Manorama, 1996 (30) | India | Children | ∼7.6 ± 0.3 y | Age | MRDR pre-/post-VA intervention in children2 | 21 | MRDR responded to the intervention |
| Tanumihardjo, 1996 (42) | Indonesia | Children | 24–70 mo | Age | MRDR 1 mo crossover test/retest with 5.3 or 8.8 μmol DR in children and time course | 34 | The higher dose increased DR:R but there was no difference in mean DR:R at either time (both doses combined). MRDR can be measured at 4–7 h in children |
| Tanumihardjo, 1996, 2004 (31, 36) | Indonesia | Children | 0.6–6.6 y | Age, infection (trichuriasis, ascariasis) | MRDR pre-/post-VA and/or deworming intervention2 in children | 308 | MRDR was not affected by deworming but responded to VA intervention |
| Tanumihardjo, 1996 (63) | Indonesia | Women | 24.7 ± 6.3 y | Lactation | MRDR 3 × 1 mo retest and pre-/post-VA intervention2 | 23 | MRDR responded to the intervention |
| Boner, 1997 (113) | Holstein | Calves | Neonatal | Age | RDR time course and varying dose size compared with biopsy TLR3 in neonatal calves | 11–16 | RDR value correlated with dose (as varying VA concentrations in 2.3 kg colostrum) but not with TLR at any time |
| de Pee, 1997 (62) | Indonesia | Lactating women | 17–40 y | Lactation | MRDR pre/post-VA or β-carotene intervention2 in lactating women | 265 | MRDR responded to intervention |
| Willumsen, 1997; Filteau, 1998 (87, 144) | South Africa | Children | ∼24 ± 10 mo | Age, inflammation, and immune response (kerosene ingestion) | MRDR in children following kerosene ingestion, and correlation with neopterin | 47 with kerosene ingestion, 45 control | MRDR not different between kerosene ingesters (80% positive) and control (67% positive). MRDR was not correlated with neopterin |
| Raghuramulu, 1998 (32) | India | Children | 1–5 y | Age, malnutrition | RDR pre-/post-intervention2 in children with 26% mild, 66% moderate, and 8% severely undernourished by weight-for-age6 | 49 | RDR did not respond to the intervention by 4–10 d |
| Biesalski, 1999 (145) | Germany | Two German teenagers and their mother | 14, 17, — | Two different RBP mutations | Single RDR in each subject | 3 | RDR was negative in all 3 (homozygous teenagers and heterozygous mother) |
| Ribaya-Mercado, 1999 (74) | Guatemala | Elderly adults | 60–81 y | Age | RDR pre-/post-VA intervention2 in elderly adults | 9 | RDR did not respond to the intervention but mean RDR was negative to begin with |
| RDR compared with RID in elderly adults | 26 | One subject had a false-positive RDR, all subjects were VA-adequate by TLR | |||||
| Rice, 1999 (6); Filteau, 1999 (140) | Bangladesh | Women | 26.6 ± 5.7 y | Lactation | MRDR pre-/post-VA or β-carotene intervention2 in lactating women, correlation with mammary permeability by treatment group | 98–106/time point | MRDR responded to intervention. Mammary permeability was correlated with MRDR but not treatment group |
| Infants | 7–21 d | Breastfeeding, age | MRDR in infants of women in different intervention2 groups | 208 | MRDR responded to the intervention | ||
| Tyson, 1999 (7) | USA | Preterm infants | GA 26.8 ± 1.8 wk | Age | i.m.-RDR post-VA intervention2 in very-low-birth-weight neonates (<1000 g) | 300 | i.m.-RDR responded to the intervention |
| Hammell, 2000 (114) | Holstein | Calves | 28 d | Age | RDR compared to liver biopsy TLR3 with time-course at 20 h postpartum or 28 d, pre-/post-intervention | 53 | RDR was correlated with dose size rather than TLR in neonates, but RDR status correctly correlated with liver stores at 28 d. RDR at 6 and 8 h, but not 4 h, correlated with TLR |
| Solon, 2000 (33) | Philippines | Children | 9.5 ± 2 y | Age | MRDR post-VA intervention2 in children | 149 | MRDR responded to the intervention |
| Ncube, 2001 (64) | Zimbabwe | Women | ∼27 ± 7 y | Lactation | RDR pre-/post-VA intervention2 in lactating women | 43 | MRDR responded to the intervention |
| Bahl, 2002 (8) | Ghana, India, Peru | Infants | 6 wk | Age, breastfeeding | MRDR pre-/post-infant and maternal VA intervention2 in infants | 544 | MRDR responded to the intervention but higher cutoffs (0.09 or 0.012) discriminated between groups more clearly. Maternal and infant supplementation were not examined separately |
| Stephensen, 2002 (34) | Peru | Children | ∼25 mo | Age, infection (pneumonia) | RDR post-VA intervention2 at discharge following pneumonia treatment, correlation with CRP | 86 | RDR responded to intervention in children with low CRP but not high CRP, 2–5 d postintervention |
| Wieringa, 2002, 2003 (10, 146) | Indonesia | Infants | 4.2 ± 0.5 mo | Age, inflammation, iron and zinc nutrition | MRDR post-VA or β-carotene and/or iron and/or zinc intervention2 in infants | 238 | MRDR did not respond to β-carotene or zinc interventions but was improved by iron interventions |
| Tanumihardjo, 2002 (70) | Indonesia | Women | 18–37 y | Pregnancy, iron nutrition | MRDR pre-/post-VA and/or iron intervention in pregnant women | 27 | MRDR only responded to VA + iron intervention |
| Ambalavanan, 2003 (9) | USA | Preterm infants | GA <32 wk | Age, BPD | 2-h i.m.-RDR post-VA intervention2 in very-low-birth-weight neonates receiving VA 3 d/wk, twice the usual dose 3 d/wk, or the usual dose concentrated into 1 d/wk | 27–30/group | i.m.-RDR was not different between groups |
| Davidsson, 2003 (35) | Cote d'Ivoire | Children | 6–12 y | Age | MRDR pre-/post-VA intervention2 in children | 13 | MRDR prevalence did not respond to the intervention |
| Feranchak, 2005 (43) | USA | Children | 0.5–21 y | Choleostatic CLD (biliary atresia, Alagille syndrome, etc.), non-choleostatic CLD (α1-antitrypsin deficiency, autoimmune hepatitis, etc.), age | Oral RDR, then i.m.-RBP-RDR and i.m.-RDR on the following day in choleostatic and non-choleostatic children with CLD, oral RDR time course | 23 choleostatic, 10 non-choleostatic | RBP-RDR at a 9-h time point had no positives but 10 h oral RDR and 9 h i.m.-RDR did. There were no positive RDRs in non-choleostatic CLD. Two children with biliary atresia had no response to oral RDR but did respond to i.m.-RDR. Oral RDR was elevated in i.m.-RDR-positive individuals by 5 h with a maximum at 10 h |
| van Jaarsveld, 2005 (37) | South Africa | Children | 7.3 ± 1.2 y | Age, inflammation | MRDR pre-/post-β-carotene intervention2 in children, correlation with CRP and AGP | 176 | MRDR responded to the intervention. Excluding children with elevated CRP and/or AGP did not affect results |
| Surles, 2006 (123) | Large White/Landrace crossbreed | Sows | 3.1 ± 0.9 y | Lactation | MRDR compared with liver necropsy TLR,3 time course including DR loss to milk | 6 | MRDR was low in VA-sufficient sows; 10–20% of dose is excreted in milk. Milk DR:R was correlated with MRDR |
| van den Broek, 2006 (71) | Malawi | Women | ∼227 [14–30] y | Pregnancy, iron deficiency | MRDR pre-/post-VA intervention2 in mostly anemic pregnant women | 530 | MRDR positive prevalence was very low and did not respond to the intervention |
| Ayah, 2007 (11) | Kenya | Infants | 26 wk | Age, breastfeeding | MRDR post-infant and/or maternal VA intervention2 | 564 | MRDR responded to infant, but not maternal, intervention |
| Idindili, 2007 (12) | Tanzania | Infants | 1.41 ± 0.96 mo | Age, breastfeeding | MRDR post-infant and maternal VA intervention2 | 166 | MRDR responded to intervention but was not different between the 2 high-dose levels. Maternal and infant supplementation were not examined separately |
| Surles, 2007 (134) | Large White/ Landrace crossbreed | Piglets | 28 d | Age | MRDR pre-/ post-VA intervention in young piglets, compared with liver necropsy TLR,3 correlation with parity | 56 | MRDR responded to intervention. The second parity of piglets had a lower TLR, which was reflected by MRDR |
| Permaesih, 2009 (65) | Indonesia | Women | ∼20–30 y | Lactation | MRDR pre-/post-VA intervention2 | 30–35/group | MRDR was lower in treatment groups vs. placebo |
| Astiazaran-Garcia, 2010 (44) | Mexico | Children | 8.9 ± 1.7 y | Age, infection (Giardia lamblia) | MRDR pre-/ post-treatment for G. lamblia in children | 30 | MRDR responded to the treatment |
| Surles, 2011 (124) | Large White/ Landrace crossbreed | Sows | 2.1 ± 0.3 y | Lactation, parity | MRDR and milk DR time course in sows after 2 or 3 parities on VA-free diet, comparison with necropsy TLR3 | 7–8/time point | MRDR was elevated after 3, but not 2, parities on VA-deficient feed, despite sufficient TLR (∼0.2 μmol/g). Milk DR:R was correlated with MRDR |
| Agne-Djigo, 2012 (13) | Senegal | Infants | ∼6 ± 0.4 mo | Age, breastfeeding | MRDR pre-/ post-maternal VA intervention2 with deuterium dose-to-mother (milk intake measured) | 32 | MRDR responded to maternal intervention despite very similar milk retinol concentration and milk intake in treatment and control |
| Ambrosio, 2012 (38) | Brazil | Children | 12–72 mo | Age | RDR pre-/post-VA intervention2 in children | 97 | RDR responded to the intervention |
| Dougherty, 2012 (39) | USA | Children | ∼8 ± 3 y | Age, zinc status, sickle cell anemia | RDR pre-/post-VA and/or zinc intervention2 in children with sickle cell anemia | 49 | RDR was very low before and after the intervention in all groups so comparisons were not possible |
| Mactier, 2012 (15) | Scotland | Preterm infants | 24–33 wk GA | Age | 3-h RDR post-VA intervention2 in preterm infants | 63 | 3-h RDR did not respond to intervention |
| Schmiedchen, 2014 (16) | Germany | Newborn infants | 3 d | Age, low birth weight | i.m.-RDR and RBP-i.m.-RDR 25-d test/retest in low-birth-weight (<1500 g) newborn infants | 63 | i.m.-RDR was not correlated with i.m.-RBP-RDR. RDR decreased over time |
| Bresnahan, 2014 (142) | Zambia | Children | 4.5 ± 0.9 y | Age, inflammation | MRDR pre-/ post-β-carotene intervention2 in children, correlation with CRP and AGP | 181 | MRDR increased in response to low VA study diet. MRDR was not correlated with CRP or AGP |
| Santana, 2016 (126) | Brazil | Adults | 24–68 y | CLD (non-cirrhotic hepatitis C), body weight | RDR compared to liver biopsy free retinol concentration3 in adults with CLD and 49% BMI ≥25 kg/m2 | 43 | All RDRs were negative and free liver retinol was adequate (some subjects just below 0.1 μmol/g). Degree of fibrosis did not affect RDR or free liver retinol |
1
AGP, α1-glycoprotein; CLD, chronic liver disease; CRP, C-reactive protein; DR, 3,4-didehydroretinol; DR:R, molar ratio of 3,4-didehydroretinol to retinol; GA, gestational age; MRDR, modified relative dose-response; RBP, retinol-binding protein; RDR, relative dose-response; RID, retinol isotope dilution; RP, retinyl palmitate; TLR, total liver reserves; VA, vitamin A.
2
See Table 2 for more details.
4
Defined by the WHO (147).
5
Defined by the National Center for Health Statistics (148).
6
Defined by Rao et al. (149).
7
Reported as median [IQR].